Autotransplantation as an Effective Therapy for the Loin Pain-Hematuria Syndrome: Case Reports and a Review of the Literature

0022-5347197/1575-15~~3.00/0 THe JOURNAL OF UnomY Copyright 0 1997 by AMERICANUROLOCICN. ~ W I A T I O N INC. .

Vol. 157, 1554-1559. May 1997 Printed in U.SA.

Review Article AUTOTRANSPLANTATION AS AN EFFECTIVE THERAPY FOR THE LOIN PAIN-HEMATURIA SYNDROME: CASE REPORTS AND A REVIEW OF THE LITERATURE AARON SPITZ, JEFFRY L. HUFFMAN

AND

ROBERT MENDEZ

From the Department of Urology, University of Southern California, Los Angeles, California

ABSTRACT

Purpose: The loin pain-hematuria syndrome is a well recognized but poorly understood clinical condition in which patients have progressive loin pain accompanied by hematuria but they maintain stable renal function. We present 2 cases effectively treated with renal autotransplantation, as well as a review of the literature, and a coherent algorithm for the diagnosis and treatment of this condition. Materials and Methods: The medical literature concerning the loin pain-hematuria syndrome was reviewed. In 1994 we performed renal autotransplantation on 2 patients with the loin pain-hematuria syndrome a t our institution. Results: Extensive urological evaluation revealed no obvious underlying abnormalities in patients with the loin pain-hematuria syndrome. Theories for the pathogenesis of this condition range from thrombotic phenomena to autoimmune processes. Treatment efforts have been directed primarily towards pain management. Narcotic dependence becomes progressive as the pain becomes debilitating. In extreme cases nephrectomy is performed despite normal renal function. Several invasive methods of nerve block and enervation provide only temporary relief. Renal autotransplantation provided lasting cessation of loin pain in both of our patients with followup of 1.5 and 2.5 years, and this intervention has been shown to provide the most durable pain relief in other series. Conclusions: Renal autotransplantation provides the most durable, nonnarcotic, nephron sparing relief for patients with the loin pain-hematuria syndrome. Further investigation is necessary to elucidate the pathophysiology of this debilitating condition. KEY WORDS:hematuria; transplantation, autologous; pain

First described by Little et a1 in 1967, the loin painhematuria syndrome presents primarily with 3 basic symptoms: 1)flank pain, 2) hematuria and 3 ) occasional low grade fevers.1 The flank pain is intermittent, varying in duration and progressive, and may be unilateral or bilateral. The hematuria is microscopic or gross and usually but not necessarily occurs with episodes of pain.' The etiology of the loin pain-hematuria syndrome is poorly understood and diagnosis is made by exclusion. Patients have normal renal function, normal radiographic and endoscopic studies of the genitourinary system, and no evidence of infection, malignancy, trauma, nephrolithiasis or renal insufficiency. Therapy is aimed primarily at relief of pain. The underlying cause is not well understood and there is no evidence of deterioration of renal function. To our knowledge no effective treatment exists for cessation of the hematuria. Pain control is progressive from nonsteroidal anti-inflammatory agents to narcotics to nerve blocks to operations. The most definitive treatment for the loin pain-hematuria syndrome is autotransplantation. Diagnosis and treatment of the loin pain-hematuria syndrome should be done expeditiously after a rational evaluation that excludes other known causes of hematuria and loin pain. Patients with the loin pain-hematuria syndrome often go years without a diagnosis and with deleterious consequences to their life-styles. These patients are often treated

with prolonged courses of narcotics before effective surgical management. CASE HISTORIES

Case 1. A 22-year-old white male college student presented in 1987 with left flank pain 2 weeks in duration characterized as stabbing pain occurring 1 to 2 times a week, lasting 2 to 3 minutes and associated with intermittent episodes of gross hematuria. He also reported occasional low grade fevers up to 100.2F. The patient denied frequency, urgency or dysuria. Medical history was significant for severe headaches, once associated with a seizure (neurology evaluation with magnetic resonance imaging was negative) and a questionable history of kidney stones at age 4 years. The patient also had a childhood history of hypogammaglobulinemia requiring gamma globulin injections. Physical examination revealed no flank tenderness or palpable masses. Urinalysis revealed microscopic hematuria and trace proteinuria. Urine culture yielded no infection. Serum chemistry studies, coagulation profiles, autoimmune studies, excretory urogram (IVP) and left retrograde pyelography were normal. A renal angiogram also showed no abnormalities. Left ureteroscopy revealed erythema with bleeding in the region of the upper pole posterior calix. This region was fulgurated and the remainder of the intrarenal collecting

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system was normal. Because bleeding and pain persisted ARer consultation the patient underwent a celiac plexus the patient underwent renal angiography and angio- block, which afforded temporary relief. Pain exacerbations embolization of the vessels feeding the posterior upper pole continued requiring repeat epidurals and parenteral narcalk of the left kidney, which were unsuccessful, and left cotics. ARer much discussion autotransplantation was upper pole partial nephrectomy was performed. performed 6 months after the initial consultation. IntraoperGross and histopathological examination was consistent ative biopsy appeared normal by light and electron microswith recent and remote infarction, recurrent ischemic events copy. Of unknown significance was a finding of abundant, and vascular malformation. The pain and hematuria re- large nerve trunks in the perivascular tissue of the right solved but after 3 months similar symptoms occurred in the renal arterial cuff. The patient was pain-free for 16 months contralateral kidney, progressing to incapacitating pain. Re- with occasional gross hematuria. peat cystoscopy and bilateral retrograde pyelography were unremarkable. Ureteroscopy was attempted but the ureteroEPIDEMIOLOGY scope could not be passed the full length of the right ureter. There have been approximately 220 reported cases of the Repeat renal ultrasound was normal. The patient was treated with aminocaproic acid without cessation of the epi- loin pain-hematuria syndrome in the literature since the sodic hematuria and pain. He also received 25 mg. indometh- description by Little et al of 3 female patients in 1967.1 acin orally twice daily. Within 1 month the pain medication Several early studies overlapped reported cases 80 the numwas advanced to oxycodone hydrochloride plus acetamino- ber is not entirely clear. Initially the loin pain-hematuria phen twice daily. The pain specialty service added C trypto- syndrome was described as a condition affecting only fephan in hopes of decreasing pain by increasing central sero- male patients until Habte et al reported the syndrome in tonin supplies. Pain persisted and a celiac plexus block was 3 male patients in 198L2The condition is still predominantly performed with adequate but temporary results. Because of reported in female patients. The age at onset of the loin the severity of pain, surgical enervation of the right kidney pain-hematuria syndrome ranges from early adulthood to middle age, and it can arise as early as age 16 years in either was performed. A wedge biopsy obtained intraoperatively revealed no ab- sex with the majority of cases arising in the mid 20s to early normalities under light microscopy. Electron microscopy 30s.Information is lacking regarding race but most patients demonstrated only membrainoid structures in glomerular are reported from the British Isles, Australia and Canada basement membranes and focal ectasia of peritubular capil- Most patients have no significant medical or family history. laries. By 2 months after enervation the patient was com- Some studies describe a n association with the use of pletely pain-free on the ipsilateral side. However, occasional oral estrogens. Burden et al described 6 of 13 women on oral pain developed in the left flank again but without gross estrogens with relief of symptoms in 3 after cessation hematuria. By 4 months aRer enervation the patient was of estrogen.3 Associations have been suggested with patient still pain-free on the right side but left loin pain had become involvement directly or indirectly through marriage within intolerable. Left renal enervation was attempted but because the health care professions: 4 of 10 patients reported on by of scarring and adhesions left nephrectomy was performed. Chin4 and 4 of 13 reported on by Burden et a13 were nurses, Gross and histopathological examination was similar to that while Aber and Higgins reported that 10 of 51 were nurses or from the previous left partial nephrectomy, and there were wives of physicians,6 and Lucas et al stated that 7 of 15 had also findings of some vascular wall thickening. The patient a paramedical background.6 remained pain-free without hematuria for 4 months. PRESENTATION Right flank pain recurred 8 months aRer left nephrectomy and by 15 months after right enervation the right loin pain The presentation of the loin pain-hematuria syndrome was had become intolerable. A psychological evaluation revealed first described by Little et al and has been similar in all no abnormalities. Autoimmune and coagulation panels again reported cases.' The loin pain can be unilateral or bilateral were normal. By 2.5 years postoperatively the patient had with varying duration ranging from only a few minutes to a suffered episodic severe right flank pain and hematuria re- constant ache lasting months. The pain varies in frequency quiring multiple hospitalizations for parenteral narcotics. from only once or twice a year to incessant, and it may Epidural anesthesia afforded good but temporary relief. Re- radiate to the groin,7 iliac fossa or anterior thigh.2 The pain nal angiography revealed only questionable renal hypovas- is usually not associated with position or movement. Hemacularity of the inferior right pole. After extensive therapy turia is often gross but it frequently alternates with microwith pain medication for 4 years after right renal enervation, scopic hematuria and it is sometimes, although not necessarthe patient underwent renal autotransplantation from the ily, temporally related to episodes of loin pain. Other right flank to the left iliac fossa. He has been pain-free for 2.5 symptoms include occasional low grade fever,l.s-lo freyears with occasional episodes of hematuria. quency, urgency,lo.11 nausea and vomiting, of which only low Case 2. A 25-year-old white male computer programmer grade fever is common. first presented in 1984 with right flank pain and hematuria. Symptoms resolved until October 1992. IVP and retrograde PHYSICAL FINDINGS Pyelography were normal. Symptoms again resolved until Many patients have an unremarkable physical examinaApril 1994. After 1 month of right flank pain and hematuria the patient was referred to our care. He took ibuprofen and tion. Several investigators reported mild to severe loin tenoccasional oxycodone for the loin pain. Medical history was derness on the affected side.1.2.8.10.12.13Many patients report low grade fevers and almost every patient is normotensive Significant only for appendectomy. On physical examination the patient was normotensive with normal renal function according to serum creatinine and had mild right loin tenderness. Urinalysis revealed trace and creatinine clearance. When examined the concentratProtein and scant blood. Urine culture yielded no infection. ing and acidifying capacities of the kidneys are normal.' Serum chemistry studies, coagulation profiles, autoimmune Burdens and Sieglerlo et al found no abnormal 24-hour urine studies, IVP, retrograde pyelography, ureteroscopy, comput- concentrations of calcium, phosphorus, uric acid, cysteine erized tomography, and renal scans were normal. A renal and oxalate. Patients manifest no or occasionally moderate proteinuria during attacks of gross hematuria. Urine miangiogram revealed no abnormalities. Before consultation with the patient the flank pain had scopic examination reveals normal or dysmorphic red blood Progressed and became debilitating, requiring several hospi- cells.11-12'14.15 Red blood cell casts, granular casta and abtal admissions for pain control with parenteral narcotics. sence of casts have been noted.10.1Z Occasional white blood

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AUTOTRANSPLANTATION AS EFFECTIVE THERAPY FOR LOIN PAIN-HEMATURIA SYNDROME

cells have been reported.'* Urine culture is always negative, even when followed for several years.14

months) there was evidence of progression from local isch. emia to renal scarring.'." PATHOLOGY

HEMATOLOGY

Coagulation studies are usually normal. Bleeding time, prothrombin time, partial thromboplastin time, platelet count and hematocrit have been within normal limits except for occasional patients with iron deficiency anemia.13. l 4 Burden et a1 observed normal plasma clottable fibrinogen and fibrin degradation products before and during an attack of the loin pain-hematuria syndrome." Some abnormalities of coagulation have been reported. Burden et a1 described a decrease in platelets, increase in schistocytes and decrease in hemoglobin in blood aspirated directly from the renal vein compared to blood from the vena cava, as well as a shortened heparin thrombin clotting time." Parbtani and Cameron noted an increase in free plasma serotonin concentrations but normal intra-platelet serotonin concentrations, implying consumption of platelets locally within the kidney. l6 Aber and Higgins reported persistently elevated factor 111 and decreased platelet life-span, which seemed to be linked to exogenous estrogen.5 Others noted increased platelet aggregation in the serum.10.13 Siegler et a1 found that serum in these patients had an impaired ability to support prostaglandin I2 production by cultured human umbilical vein endothelial cells.10 Prostaglandin I2 is a potent antiplatelet and antithrombotic substance normally released by vasculoendothelial cells. Siegler et a1 also noted mildly elevated fibrinopeptide A levels and circulating antiplatelet antibodies.10 In 1 patient serum from the renal vein was compared to that taken from the inferior vena cava, which revealed elevated fibrinopeptide A locally in the blood draining the kidney.") Leaker et a1 also found elevated circulating platelet aggregates and increased platelet sensitivity as measured by adenosine diphosphate threshold.14 Decreased factor XI1 was reported in 1 patient.13 GENITOURINARY IMAGING

The initial evaluation of patients by Little et a1 included IVP, cystoscopy, retrograde pyelography and renal angiography.1 Abnormalities were noted only on renal angiography. All subsequent investigators reported normal results on IVP, cystoscopy,l-4.7.H.l'. 13.17.1Rretrograde pyelography,l.3.4 renal ultrasound,4.13.18 computerized tomographyl~4,8~ l1, 13,17,18 and renal scan4.13.15.19 except for Leaker et al, who found that 2 of 25 patients had mild unilateral obstruction on IVP, which spontaneously resolved,14 and Dimski et al, who found interstitial cystitis at cystoscopic examination in 1 patient.12 Renal angiography was described as abnormal in the initial series by Little et al, with changes including focal disorganization of peripheral renal arteries with relatively avascular areas of renal parenchyma and smaller arteries ending abruptly, some with a gnarled, tortuous appearance.' These findings were duplicated consistently by subsequent investigators.".H.17.20 Proximal arteries were normal but structural lesions were evident in interlobar, interlobular and arcuate arteries. Burden et a1 noted angiographic abnormalities occasionally on the nonaffected side and always on the symptomatic side.HIn 1981 Habte et a1 reported the first 3 cases with normal renal angiograms" and most investigators, with few exceptions,4." 1:' have since found no abnormalities on renal angiographyZ.7.1"-1". 15.21.22 or only transient ischemic changes.1*.*:3Before Habte et a1 reported normal renal angiography," Fletcher et al noted some reversible as well as . ~ ~ found irreversible disturbances of cortical p e r f ~ s i o n Guyer that injecting higher osmotic contrast medium in patients with the loin pain-hematuria syndrome revealed vascular abnormalities and triggered attacks of pain.zo Early investigators stressed that on followup renal angiography (15 to 24

Gross and microscopic abnormalities have been inconsistent when present. No abnormalities were found in several patients.4.7.24 Few gross specimens have been available. There are reported findings of cortical ischemia and infarct as well as intimal arterial lesions from segmental arteries distally. In regions of infarct the feeding arteries sometimes had evidence of previous occlusion and recanalization as well as lesions of the internal elastic lamina.I7 Histopathological study may demonstrate nonspecific findings. Mild to moderate proliferation of the mesangial matrix was the most consistently found abnormality of the nephron.2-4.R.10-1~15.18.21 Other findings included ischemic or fibrotic glomeruli,l. 17.21 occasional tubular atrophy,1.3.12.17fibrinous deposits in glomeruli,' and cortical ischemia and infarct seen as scattered foci of interstitial fibrosis.1.14.17.21Renovascular lesions were frequent, particularly in the peripheral vessels, and included occasional scattered arterioles with fibrous intimal thickening, fibroelastic hyperplasia and concentric cellular thickening in arterial walls.' Arteriolar hyalinosis and microaneurysms were noted.3,5.10,12.14, 18,25 Lesions of the renal vasculature and renal parenchyma were not necessarily associated with the condition. Electron microscopy was performed by a few investigators with nonspecific findings, including focal foot process fusion, glomerular basement membrane wrinkling7 and fibrin deposition in glomerular afferent arteriole^.^ Frequently no abnormalities were found on electron microscopy.2.s. 12 IMMUNOHISTOCHEMISTRY

Burden et a1 first explored a possible immune mediated pathogenesis for the loin pain-hematuria syndrome.3 They examined renal biopsies with immunohistochemical stains in 14 patients, and found complement 3 (C3) deposition in arteriolar walls of all specimens to varying extents and in the glomerular basement membrane of half of the specimens. From 1975 to 1990 most investigators performed immunohistochemical staining of biopsy specimens and the majority found C3 deposition in arteriolar w a l l ~ . ~ ~ ~ - ~ ~ ' 1 ~ 1 ~ In 1990 Leaker et a1 reported only 1 of 25 renal biopsy specimens to have positive C3 staining.14 Chin reported 2 of 3 patients to have negative stains.4 However, Talic et a1 recently reported a nephrectomy specimen to show C3 deposition throughout the blood vessel walls from the interlobular arteries to the afferent arterioles.15 C3 is often associated with a variety of pathological renal processes and is not considered a specific finding. Of note only in rare instances are any immune complexes other than C3 seen in these patients.2.12 Other complexes include immunoglobulins G, M and A, and fibrinogen.2.10.12.13 To our knowledge evidence of a systemic autoimmune process has never been found in patients with the loin pain-hematuria syndrome. Beginning with the landmark study, Little et all and all subsequent investigators found no abnormalities in serum antinuclear antibody titers, lupus erythematasus cell preparation or sedimentation rate. Burden et al additionally noted only normal AS0 titers.8 Complement levels, rheumatoid factor,2 antideoxyribonucleic acid antibody titers and serum protein electrophoresis were normal when studied.24 Bell et a1 raised the possibility of a renal manifestation of hypersensitivity, noting severe hypersensitivity type 3 reaction in all 10 patients with the loin pain-hematuria syndrome when tested with each of a variety of recall agents.24 DISCUSSION

Both cases presented are typical of the loin pain-hematuria syndrome as previously characterized and both presented

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with flank pain and hematuria that progressed in intensity coagulopathy does not seem to be important in the pathogento the point of debilitation. Physical examination was unre- esis of the loin pain-hematuria syndrome. There may be a markable. Renal function remained normal in both cases. possibility of localized microthrombotic events occurring in Neither patient manifested any significant abnormalities in patients but to our knowledge this has not been assessed regard t o coagulation, autoimmunity, uroradiographic find- adequately in a controlled study. In early studies structural ings, or gross or histopathological studies. Electron micros- vascular lesions were identified on pathology specimens and copy revealed mild abnormalities of the basement mem- renal angiograms as described previously.'," In addition to brane, which is in keeping with the findings of others such as immunogenic factors, vasospasm was suspected as having a wrinkling of the basement membrane and fusion of the foot role in the pathogenesis of these lesions. Little et a1 postuprocesses. Immunohistochemical stains were not performed lated intense vasospasm as a possible explanation of the as part of evaluation. Of interest is the finding of large intermittent symptoms but they also characterized the synabundant nerve trunks in the perivascular tissue at renal drome as involving permanent pathological changes in vesautotransplantation in case 2. This finding was also docu- sels and the interstitium.' Others also agreed that structural mented by Talic e t a1 in a graft nephrectomy performed after vascular lesions were inherent in the pathophysiology.lO.17.20 autotransplantation.l5 Leaker et a1 proposed that vasospasm may lead to the vasPathogenesis.Although the loin pain-hematuria syndrome cular lesions that were similar to those seen in cases of is well characterized, it is poorly understood. Based on his- cyclosporin toxicity, also believed to be secondary to vasotological and angiographic evidence of ischemia and vascular spasm.14 Burden et a1 stated that angiographic findings were abnormalities, early investigators postulated that v a s e the only way in which the clinical diagnosis could be conocclusive episodes were the cause of symptoms.l.3~~.1o.l4.17.~~25 firmed.3 Others proposed that these vascular lesions noted on Thrombosis was postulated as a possible etiology of vascular x-ray may merely indicate vasoconstriction, perhaps as insult. Estrogen related coagulopathy was proposed a s con- a consequence of the contrast material itself.23 However, tributing to the pathogenesis for the loin pain-hematuria Bergroth e t a1 noted that the occurrence of vasospasm during syndrome by early investigators who believed that the syn- renal angiography was more frequent than could be exdrome affected women only. Even without reports of male plained by mere coincidence.18 Other investigators found no cases the link to exogenous estrogen could not explain the evidence of vascular lesions or spasm on pathological exampresence of the syndrome in women who were not taking ination or angiography and deny such findings as being sigbirth control pills. Several uncontrolled studies explored the nificant to the diagnosis or pathogenesis of the loin painpossibility of microthrombotic and microembolic phenomena hematuria syndrome.2.s Regarding our 2 cases there was occurring locally in the kidney, pointing to the detection evidence of vascular thickening in case 1 and no abnormaliof possible by-products or sequelae of intravesical coag- ties in case 2, and neither had any evidence of vaso-occlusion ulation.10 or structural lesions on angiography during initial evaluaBurden e t a1 examined the serum from the renal vein of 1 tion. Overall, such findings, if positive, are nonspecific. Vaspatient and found increased platelet aggregation, decreased cular occlusion and structural damage are not necessary hematocrit and increased fragmented red blood cells com- findings and should not be criteria for diagnosis of the loin pain-hematuria syndrome. pared to blood sampled from the inferior vena ~ a v a They .~ Theories about a possible autoimmune etiology of the loin also recorded decreased heparin-thrombin clotting time in 7 of 8 patients with the loin pain-hematuria syndrome, imply- pain-hematuria syndrome have been stimulated by frequent ing increased platelet factor IV a ~ t i v i t y This . ~ assay is now findings of complement deposition in renal specimens. Early outmoded and is confounded by other circulating heparin investigators consistently demonstrated C3 deposition in reagonists.27 Siegler et a1 also studied renal vein samples in 1 nal arteriolar walls and Burden et al stated that such presPatient and found increased concentration of fibrin peptide ence characterized the syndrome.3 Some considered the A, suggesting platelet activity and fibrin deposition inherent presence of C3 to indicate vascular damage,'* which would in the pathogenesis of the loin pain-hematuria syndrome.1° imply a vascular etiology to the syndrome.7 C3 deposition is They also noted sluggish platelet aggregation implying that not always present and even when present its significance is Platelets were exhausted from previous activation within the questionable. The presence of complement with or without kidney. Prostaglandin I2 is a potent antiplatelet, antithrom- immunoglobulin in vessel walls is normally found in a wide botic substance normally released by vasculo-endothelial variety of renal disorders and is not specific.R We did not cells. Siegler et a1 reported a n inability of patient serum to examine the specimens from our 2 patients with immunohisSupport prostaglandin I2 by cultured endothelial cells, which tochemical stains. The findings appear to be nonspecific and may be secondary t o a primary defect of the endothelium to sporadic, and are not necessary for diagnosis of the loin Produce prostaglandin 12 in response to a vascular insult pain-hematuria syndrome. Intermittent urinary obstruction (toxin, virus), or it may be secondary to consumption of a was ruled out in a case controlled nuclear scan study that Prostaglandin I2 supporting factor secondary to present vas- failed to demonstrate disordered urinary peristalsis in pacular damage.10 In either case the condition would predispose tients with the loin pain-hematuria syndr0me.1~ The presence and progression of pain in the loin painto thrombus formation. A case controlled study demonstrated elevated free serum serotonin but normal platelet serotonin hematuria syndrome are not well understood but are related In Serum from patients with the loin pain-hematuria syn- to the autonomic nervous system, which provides innervation drome, implying local consumption of platelets in the renal to the kidney. The pain of the loin pain-hematuria syndrome microcirculation with liberation of serotonin into the circula- may be secondary to capsular stretching caused by parenchytion.'' Another study showed an increase in 51-chromium mal swelling due to some underlying cause, such as vascular labeled platelets in the kidney in patients with the loin injury,28 or it may be a result of direct stimulation from Pain-hematuria syndrome who were taking oral estrogen.27 vascular injury. The severity of pain is not proportional to In contrast, Leaker et a1 found evidence against thrombus that found in other conditions affecting renal vasculature or formation, with no abnormalities noted in coagulation inhi- interstitium, such as renovascular hypertension and glomerbition protein c, antithrombin 111, blood rheology or fibnno- ulonephritis, whose symptoms are much less severe but lfliCS.14 Other investigators doubt the involvement of a whose pathological findings are much more marked.12 The severity of pain may be related to a n abnormally increased thrombotic process.1.2 Our patients showed no evidence of coagulopathy on ex- density of renal artery innervation. Our case 2 had abundant tenswe hematological evaluation and there was no evidence periarterial nerve trunks of unclear pathological si@cance. Abundant nerve trunks may have been present in Of microthrombus formation on biopsy specimens. Systemic

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deterioration of renal function despite severity and duration of symptoms."' The etiology of the disease is poorly understood. Medical treatments have been derived from various theories of pathogenesis. Treatments targeting a possible coagulopathic etiology include antiplatelet therapy, such as sulfinpyrazone, which was ineffectual;", l 4 warfarin, which provided only temporary partial relief in some patients;7 dipyridamole, which had to be discontinued secondary nose bleeds;'" low dose aspirin, which was ineffectual,'" and discontinuation of birth control, which resulted in a complete response in a small number of patient^."^ In our case 1 use of aminocaproic acid proved to be ineffective with regard to hematuria. Other attempted treatments targeted a possible vasoconstrictive etiology. j3-Blockers afforded no response.14 Additional treatments include chronic vitamin E therapy and chronic antibiotics.' Unable to reverse the underlying process, all care providers have resorted to analgesics to treat the pain. Episodes of pain begin intermittently and are often of brief duration but then progress in frequency, duration and intensity. Analgesia requirements increase from oral agents, such as oxycodone hydrochloride plus acetominophen, to parenteral narcotics necessitating periodic and frequent hospitalization. Many patients become addicted to the high dose narcotics they require to function. Nerve blockade has had varying efficacy but it never afforded permanent relief. Transcutaneous electrical nerve stimulation has been disappointing.12-2s Epidural blocks have resulted in good, temporary relief in some cases, a s in our patient. Splanchnic nerve block was demonstrated to eliminate pain for u p to 3 weeks at most. Dorsal rhizotomy has been shown to provide pain relief for 3.5 months. Dorsal column spinal cord transection resulted in lasting b u t incomplete pain relief.12 Celiac plexus block resulted in adequate but brief pain relief in 1 of our patients. Intercostal nerve block has not been helpful.25 Surgical renal enervation, which was attempted in our case 1, results in complete relief of symptoms but with recurrence within 4 to 8 months.I.8 Blacklock reported renal enervation coupled with incision of the renal capsule to diminish any pain that might arise as a result of capsular distension but there was no reported followup in this case.28 Nephrectomy provided complete, durable relief of pain but this alternative is obviously undesirable, since t h e kidneys of these patients function normally. Nephron sparing therapy is preferred. Urine culture I)infection Renal autotransplantation is a n extension of t h e idea of renal enervation. I t is assumed that enervation fails because of reinnervation. It is believed that autotransplantation may our urine I)glomerular disease provide more permanent results because all nerves in the renal hilum are completely severed. Renal autotransplantalVPl Ultrasound stonel tumorlcystl etc. tion to the ipsilateral iliac fossa was first described by Aber and Higgms in 1982," and several investigators have performed this procedure." After autotransplantation pain Qstoscow* stonel tumor/ cystitis/ etc. due to the loin pain-hematuria syndrome ceases immediately. Most patients are back to work and off all narcotics Brig-*A-V malformation, hemangioma within only a few weeks:I.Z' A minority of patients experience relapse of pain a t the graft site.lZ.l"~2'".:~" Chin reported J-b approximately a 25% relapse rate in a series of 22 patients k ureteroscopy ureteral pathology (personal communication). The interval between relapse ranged from 4 to 10 months15,26iwith occasional recurrences as early a s a few weeks.12 These early recurrences may be ion studies* coagulopathy outliers. A few unfortunate patients will require graft nephrectomy secondary to the intensity of the recurrent evaluation @ factitious disease pain..'. 1 5 , Z h . :io A significant number of patients have progression of symptoms to the opposite kidney.':' l i "5 '3'' Chin reJ-L ported that 30s; of 22 patients had progrcssion to the oppoN e r v e M Loin Pain Hematuria Syndrome site side which, coupled n i t h patients presenting with hilateral symptoms, hrings t h e cohort of p a t i e n t s nit11 hilatDiagnostic aljiorithm for loin pain hcmaturia syndrome. Flcxitilr era] symptoms to 66'; (pC'lS(JIlal coinlnllnlcation 1. This findurcterosco \. i.1 perfrwrncd ns descrihcd by B n g I ~ yD:H. . and Kittenhrrg. M.c.:uro'i&., 27: :1:<1.198fi.A-V. arteriovcnous. ing often occurs within only a few rnonths to 1 yc:ir after

other patients although to our knowledge this was not specifically noted or addressed in other series. Recurrent pain at the transplanted graft site may be due to regeneration of these large nerve trunks. Talic et al found large abundant nerve trunks in a graft nephrectomy performed for recurrent pain after renal autotransplantation.15 A minority of investigators consider the pain of the loin pain-hematuria syndrome to be due to a somatization disorder or factitious.". 25) Some point is made to the preponderance of patients associated with health care professions, directly or through marriage, as a predisposing factor to such behavior. There have been reports of factitious hematuria,s but this may well be t h e attempt of the patient to gain more attention for a real ailment from physicians who become disinterested with t h e confounding subjective complaints. Many investigators, including ourselves, place patients through a psychological screen and have found them to be fully intact or experiencing a reactive depression as a consequence rather than a cause of t h e pain.4.11.22.2fi Diagnosis. The patient with the loin pain-hematuria syndrome often remains unrecognized, and frequently is neglected or shuflled from urologist to urologist until the appropriate diagnosis is finally made and adequate therapy is initiated. Diagnosis of t h e loin pain-hematuria syndrome is made by exclusion, since the pathogenesis remains a mystery. The differential diagnosis for loin pain and hematuria is extensive and a logical algorithm is required to exclude efficiently all other possibilities. Other causes of loin pain coupled with hematuria include ureteral obstruction, pyelonephritis, malignancy, benign masses, cyst rupture, infarction, immunoglobulin A nephropathy, thin glomerular basement membrane disease, arteriovenous fistula, acute renal vein thrombosis, acute arterial occlusion, entrapment of the left ren d vein between the superior mesenteric artery and aorta, renal sinus lipomatosis, and parasitic infection with Dioctophyma renale.27 The figure shows a coherent diagnostic algorithm for diagnosis and treatment of the loin painhematuria syndrome. Treatment and prognosis. Patients with the loin painhematuria syndrome frequently remain undiagnosed and inadequately treated for years. The duration of symptoms before treatment has ranged from 6 months to 19 year^.".^,^ Long-term followup exceeding 30 years shows no evidence of

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AUTOTRANSPLANTATION AS EFFECTIVE THERAPY FOR LOIN PAIN-HEMATURIA SYNDROME autotransplantation o r r e n a l e n e r v a t i o n . Several patients subsequently h a v e u n d e r g o n e a second a u t o t r a n s p l a n t a t i o n (Chin, personal c o m m ~ n i c a t i o n ) . ~ .15.20.25.30 One p a t i e n t with bilateral a u t o t r a n s p l a n t s had p a i n at both graft sites necessitating b i l a t e r a l g r a f t nephrectomy, r e n d e r i n g her dialysis dependent.l5 There are rare cases of p a i n r e c u r r i n g in the ipsilateral loin ( C h i n , p e r s o n a l communication).12 H e m a turia always p e r s i s t s , and often i s gross and i n t e r m i t t e n t in nature. W i t h followup exceeding 8 y e a r s a u t o t r a n s p l a n t a t i o n is the most d u r a b l e , nonnarcotic, n e p h r o n s p a r i n g t r e a t m e n t available ( C h i n , personal communication). Recurrent p a i n at the g r a f t site m a y be a consequence of reinnervation. Allograft s t u d i e s h a v e shown evidence of reinnervation w i t h i n 8 months.'" This explanation m a y n o t be satisfactory for the few c a s e s that r e c u r within only a few weeks.l2 Interestingly, u p t o 30% of cases will resolve spontaneously b y an average of 3.5 years according to a followup study of 51 patient^.^

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young women: diagnostic pitfalls. Brit. J . Urol., 54: 209, 1982. 8. Burden, R. P., Dathan, J . R., Etherington, M. D., Guyer, P. B. and MacIver, A. G . :The loin-paid haematuria syndrome. Lancet, 1: 897, 1979. 9. Naish, P. F., Aber, G . M. and Boyd, W. N.: C3 deposition in renal arterioles in the loin pain and haematuria syndrome. Brit. Med. J . , 3: 746, 1975. 10. Siegler, R. L., Brewer, E. D. and Hammond, E.: Platelet activation and prostacyclin supporting capacity in the loin pain hematuria syndrome. Amer. J. Kidney Dis., 12: 156, 1988. 11. Hutchison, S. M., Doig, A. and Jenkins, A. M.: Recurrence of loin painhaematuria syndrome after renal autotransplantation. Lancet, 1: 1501, 1987. 12. Dimski, D. S., Hebert, L. A,, Sedmak, D., Ogrodowski, J. L., Elkhammas, E. A., Tesi, R. J . , Gold, M. and Courville, C. S.: Renal autotransplantation in the loin pain-hematuria syndrome: a cautionary note. Amer. J. Kidney Dis., 20: 180, 1992. 13. Smellie, S. W., Lambert, M., Lavenne, E. and van Cangh, P. J.: Factor XI1 deficiency associated with loin painhaematuria syndrome. Lancet, 2 1330, 1987. 14. Leaker, B. R., Gordge, M. P., Patel, A. and Neild, G . H.: HemoCONCLUSIONS static changes in the loin pain and hematuria sydrome: secondary to renal vasospasm. Quart. J. Med., 7 6 969, 1990. The etiology of the loin p a i n - h e m a t u r i a syndrome r e m a i n s 15. Talic, R. F., Parr, N. and Hargeave, T. B.: Anephric state after unclear but the p r e s e n t a t i o n is well characterized. Earlier graR nephrectomy in a patient treated with renal autotransidentification of p a t i e n t s with the loin p a i n - h e m a t u n a synplantation for bilateral metachronous loin painlhematuria drome is i m p o r t a n t t o decrease u n n e c e s s a r y evaluation and syndrome. J. Urol., 1 5 2 1194, 1994. referrals, as well as the morbidity of this progressive condi- 16. Parbtani, A. and Cameron, J. S.: Platelet involvement in lointion. Analgesia i s the m a i n s t a y of treatment but it often painhaematuria syndrome. Lancet, 1: 1413, 1979. becomes inadequate t o provide satisfactory relief and allow a 17. Fletcher, P., Al-Khader, A. A,, Parsons, V. and Aber, G . M.: The pathology of intrarenal vascular lesions associated with the normal life-style. Surgical i n t e r v e n t i o n is the only proved loin-pain-haematuria syndrome. Nephron, 2 4 150, 1979. means of effective, nonnarcotic p a i n relief. Renal enervation is not an acceptable intervention due t o its s h o r t lived effect. 18. Bergroth, V., Konttinen, Y. T., Nordstrom, D. and Laasonen, L.: Loin pain and haematuria syndrome: possible association with Nephrectomy i s undesirable, since the syndrome does n o t intrarenal arterial spasms. Brit. Med. J., 294: 1657, 1987. compromise n o r m a l renal function. A u t o t r a n s p l a n t a t i o n pro19. Woolfson, R. G., Lewis, C. A., Hill, P. D., Hilson, A. J. and Neild, vides the m o s t d u r a b l e results, while preserving nephrons. G . H.: Ureteric peristalsis studies in loin pain and haematuria There is a long-term success rate of approximately 75%. syndrome: another diagnostic disappointment. Brit. J. Urol., Patients must be f o r e w a r n e d of a 25% relapse rate and a 30% 7 2 291, 1993. chance of s y m p t o m s o n the c o n t r a l a t e r a l side, and t h e y m u s t 20. Guyer, P. B.: Radiology of the loin pain-haematuria syndrome. be counseled a b o u t the possible need for nephrectomy or, in Clin. Rad., 2 9 561, 1978. 21. George, C. R.: Familial association of polycystic kidneys, horserare cases, bilateral n e p h r e c t o m y and dialysis dependence. shoe kidney and loin-pain-haematuria syndrome. J. Roy. SOC. h a l y s i s of w h i c h p a t i e n t s tend t o h a v e relapse would help Med., 7 4 77, 1981. the decision a b o u t w h e n t o offer autotransplantation. guide ' Further r e s e a r c h is n e c e s s a r y to elucidate the pathophysiol- 22. Sheil, A. G. R.. Ibels, L. S.. Thomas, M. A. B. and Graham, J. C.: Renal autotransplantation for severe loin-painihaematuria of t h i s debilitating condition, for example controlled studsyndrome. Lancet, 2: 1216, 1985. ies examining hematological processes locally within the kid23. Sherwood, T.: Loin painhaematuria syndrome. Lancet, 1: 1033, ney. 1979. 24. Bell, G. M., Williams, P. and Thomson, D.: Is the loin pain and REFERENCES haematuria syndrome a renal manifestation of hypersensitiv.. ity? Lancet, 1: 340, 1984. 1. Little, P. J., Sloper, J. S. and de Wardener, H. E.: A syndrome of loin pain and haematuria associated with disease of peripheral 25. Bloom, P. B., Viner, E. D., Mazala, M., Janetta, P. J., Stieber, A. C. and Simmons, R. L.: Treatment of loin pain hematuria renal arteries. Quart. J . Med., 3 6 253, 1967. svndrome bv renal autotransplantation. Amer. J. Med., 87: 2. Habte, W., Dobbie, J. W. and Boulton-Jones, M.: The loin paini28, 1989. haematuria syndrome in males. Scot. Med. J., 2 6 118, 1981. 3. Burden, R. P., Booth, L. J., Ockenden, B. G . , Boyd, w. N.. 26. Sheil. A. G . R.. Ibels. L. S.. Pollock. C.. Graham. J. C. and Short. J.: Treatment of loin painihaematuria syndrome by renal auHiggins, P. M. and Aber, G . M.: Intrarenal vascular changes in totransplantation. Lancet, 2: 907, 1987. adult patients with recurrent hematuria and loin pain-a clinical, histological and angiographic study. Quart. J. Med., 27. Weisberg, L. S., Bloom, P. B., Simmons, R. L. and Viner, E. D.: Loin pain hematuria syndrome. Amer. J. Nephrol., 13: 229, 44: 433, 1975. 1993. 4. Chin, J . L.: Loin pain-hematuria syndrome: role for renal auto28. Blacklock, A. R.: Renal denervation with releasing renal capsule transplantation. J. Urol., 147: 987, 1992. incision in the loin painlhaematuria syndrome. Brit. J. Urol., 5. A k r , G. M. and Higgins, P. M.: The natural history and man64: 203, 1989. agement of the loin painhaematuria syndrome. Brit. J. Urol., 29. Kelly, B.: Psychological aspects of loin-painihaematuria syn54: 613, 1982. drome. Lancet, 340: 1294, 1992. Lucas, P. A., Leaker, B. R.and Neild, G . H.: Psychiatric aspects 30. Harney, J., Rodgers, E., Campbell, E. and Hickey, D.: Loin of loin painlhaematuria syndrome. Lancet, 340: 1038, 1992. pain-hematuria syndrome: how effective is renal autotrans7. NicholIs, A. J., Muirhead, N., Edward, N., Mahaffy, R. G . , plantation in its treatment? Urology, 44:493, 1994. Simpson, J. G . and Steyn, J. H.: Loin pain and haematuria in