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Loin Pain Hematuria Syndrome (LPHS)

Loin Pain Hematuria Syndrome (LPHS) is an extremely rare disease, where there is unexplained flank pain and Haematuria. Often misdiagnosed as a hypermobile kidney has the same symptoms. This is poorly understood condition for which specific diagnostic criteria are lacking.

Here are some facts about LPHS:

  • LPHS was first identified in England in 1967 among women who were taking birth control pills.
  • Approximately 90% of the reported cases of LPHS are female.
  • LPHS was first noted in men in the 1980’s.
  • LPHS was first noted in the USA in the 1980’s.
  • The first renal autotransplatation for LPHS was done in 1982.
  • Cases of LPHS have been reported from England, Canada, USA, India, Australia, Ireland, Scotland and Germany.
  • The age range for LPHS is from 6 to 50 years.
  • There are approximately 200 cases of LPHS in the world; no doubt, there are more undocumentated cases.
  • Pain attacks due to LPHS can occur several times per week, every few weeks, or every few months. These pain attacks can last from hours to weeks.

    Here are some guidelines to help you decide if you think you need to investigate this problem with your doctor.

  • The condition is mainly characterized by intractable pain involving the kidney and abdominal areas.
  • Microscopic blood or blatantly obvious amounts of it can be seen in the urine. Clot retention can also occur.
  • It is extremely important that physicians recognize the need for adequate pain medication for this disorder.
  • Forcing fluids by mouth or I.V. are very helpful in decreasing the hematuria and in reducing the risk of clot retention.
  • Be prepared to see several doctors and yield to psychiatric exams before you get a correct diagnosis. This is common with any disease that is not common, such as diabetes. LPHS has only been diagnosed in a few hundred people around the entire world, so this is one disease that is not likely to pop into a physician’s head.

    related articles

    Department of Surgery, Royal Prince Alfred Hospital, Sydney, NSW, Australia. agrs@liver.rpa.cs.nsw.gov.au

    Some patients with the loin pain/hematuria syndrome suffer incapacitating flank pain. No effective therapy has been reported. Uncertainty persists concerning the authenticity of the pain and the role of surgery in treatment.

    Forty-six patients with loin pain/hematuria syndrome and intractable pain were evaluated following treatment either by renal autotransplantation (30 patients, 10 bilaterally) or by renal denervation (20 patients, four bilaterally) over a 13-year period.

    All patients had concomitant renal nerve excision and ligation and capsulotomy. There were 37 (80%) women and nine men aged 18 to 61 years (mean age, 33 years).

    Excretion urography and angiography were normal in all patients. Nineteen of 25 (76%) patients in whom renal autotransplantation was successfully accomplished and who completed a follow-up questionnaire were free of pain, including eight of 10 with bilateral procedures.

    The follow-up periods ranged from 1 to 13 years (mean, 8.4 years). Six patients have been free of pain for 10 to 13 years.

    Of 18 patients treated with renal neurectomy who were available for follow-up examination, 12 (67%) developed recurrent renal pain, including four who had pain relief on the other side following previous renal autotransplantation.

    The follow-up period for these patients ranged from 6 to 9.9 years (mean, 8.0 years). Three of four patients with recurrent renal pain following neurectomy were treated successfully by renal autotransplantation.

    The loin pain/hematuria syndrome is a rare cause of incapacitation, predominantly of relatively young females. The pain of the syndrome is organic.

    Renal autotransplantation achieves pain relief in three quarters of patients, but the procedure is often (30%) required bilaterally and has significant complications.

    Renal neurectomy is followed by an excessive incidence of recurrent renal pain.


    What is Loin Pain Hematuria Syndrome?

    by Marc F. Brazie, MD
    Division of Nephrology
    University of Maryland Medical Center, Baltimore, MD

    What is Loin Pain Hematuria Syndrome (LPHS)?

    LPHS is a rare kidney disorder causing attacks of severe flank pain and blood in the urine.

    Who gets LPHS?

    LPHS was first reported in three patients in 1967 who were found to have recurrent attacks of severe flank pain and blood in the urine (hematuria) in whom no other explanation could be found [2]. Since that time, it has been reported in several hundred people worldwide, although it is likely that there are many more unreported cases. It is more common in women (70% of all cases) [3-5], and has been seen mostly in the United States, Great Britain, Australia, and Canada, suggesting a white predominance. While it can start at almost any age, most patients will first develop symptoms in their 20’s [6].

    How do I know if I have LPHS?

    The predominant features of LPHS are recurrent flank pain and blood in the urine. The pain can occur on only one side or both, and may radiate to the abdomen, groin, or inner thigh. Pain episodes may be associated with low-grade fevers and a burning discomfort with urination. The blood in the urine may be overt (called “macroscopic hematuria”), or only detectible on a urine dipstick test or by examining the urine through a microscope (called “microscopic hematuria”). Up to 47% of patients with LPHS also have a history of kidney stones [7], but stones must be absent during pain episodes for LPHS to be diagnosed.

    What causes LPHS?

    As LPHS is a rare disorder, not much is known about the underlying causes. It is thought that there may be a problem with the glomerular basement membrane (GBM), which is the blood “filter” in the kidney, causing bleeding into the kidney tubules. These tubules can then become blocked by the blood cells, causing swelling and increased pressure in the kidney. This in turn leads to stretching of the outer layer of the kidney, called the “capsule,” and pain. Indeed, studies examining biopsies of patients thought to have LPHS have shown that in over 50% of patients, the GBM is abnormally thick or thin [7].

    What should I do if I think I might have LPHS?

    There are many disorders that can cause flank pain and blood in the urine, and as there is no specific test to confirm LPHS, it is considered a diagnosis of exclusion. It is very important to have a thorough evaluation by a kidney doctor (nephrologist) to be sure there is no other cause for the symptoms. This evaluation may involve laboratory tests, radiology studies, or even a kidney biopsy.

    What can be done for LPHS?

    Again, as LPHS is a rare disorder, it is not clear what the optimal treatment is. What is known is that patients with LPHS tend to have normal kidney function, which does not deteriorate over time. Thus, treatment is aimed at pain control and improvement in quality of life. Multiple therapies have been tried, all with mixed results. These include:
    • Medications such at angiotensin-converting enzyme inhibitors (a family of blood pressure medicines which reduce the pressure in the kidney and have been shown to be of benefit to some patients [8]), non-steroidal anti-inflammatory drugs (such as ibuprofen, naproxen, or ketorolac), and narcotic pain medications.
    • Nerve block procedures to decrease the pain signal from the effected kidney, and
    • Surgery to strip the nerves from the kidney, “autotransplant” the kidney (in which it is removed from its normal position and reinserted in the lower abdomen – this has been shown to relieve pain in up to 70% of patient in some reports [3,4]), or in extreme cases, remove the kidney altogether.

    It is best to discuss all the treatment options with your doctor, and ideally as part of a “multidisciplinary” approach involving primary care doctors, nephrologists, psychiatrists, and chronic pain specialists.


    References
    1. Dube GK, Hamilton SE, Ratner LE, Nasr SH, Radhakrishnan J. Loin pain hematuria syndrome. Kidney Int. 2006; 70: 2152-2155.
    2. Little PJ, Sloper JS, deWardener HE. A syndrome of loin pain and haematuria associated with disease of peripheral renal arteries. Q J Med. 1967; 36: 253-259.
    3. Sheil AG, Chui AK, Verran DJ et al. Evaluation of the loin pain/hematuria syndrome treated by renal autotransplantation or radical renal neurectomy. Am J Kidney Dis. 1998; 32: 215-220.
    4. Chin JL, Kloth D, Paulter SE, Mulligan M. Renal autotransplantation for the loin pain-hematuria syndrome: long-term followup of 26 cases. J Urol. 1998; 160: 1232-1235.
    5. Greenwell TJ, Peters JL, Neild GH, Shah PJ. The outcome of renal denervation for managing loin pain haematuria syndrome. BJU Int. 2004; 93: 818-821.
    6. Weisberg LS, Bloom PB, Simmons RL, Viner ED. Loin pain hematuria syndrome. Am J Nephrol. 1993; 13: 229-237.
    7. Spetie DN, Nadasdy T, Nadasdy G, et al. Proposed pathogenesis of idiopathic loin pain-hematuria syndrome. Am J Kidney Dis. 2006; 47: 419-427.
    8. Hebert LA, Betts JA, Sedmak DD, et al. Loin pain-hematuria syndrome associated with thin glomerular basement membrane disease and hemorrhage into renal tubules. Kidney Int. 1996; 49: 168-173.

  • Medications

    ANALGESICS.

    i) Non-steroidal anti-inflammatory drugs (NSAIDs) have been used for 150 years in Europe, and probably for a great deal longer in the East, in the form of willow bark extract. Useful when given appropriately, examination of the chronic pain population indicates that a very high number of patients are intolerant to these drugs because of gastrointestinal or other side-effects. There are two possible hypotheses for this. Firstly, chronic pain sufferers tend to be somewhat hypochondriacal and intolerant of body symptoms in general and thus less tolerant of real or perceived side-effects when taking medication. The second is that there may be a sub-group of patients whose pain is not managed well early on. NSAIDs may produce side-effects, limiting their use. With no pain relief, the patient fails to exercise. This hampering of their rehabilitation because of inadequate analgesia may contribute significantly towards the chronicity.

    Recently COX2 antagonists have come on the scene, but the first wave of these have been disappointing in the UK, in that the side-effect profile does not appear to be particularly better than the present drugs (Meloxicam, Etodolac). The newer drugs, Vioxx and Celebrex, are now available in the USA and will soon become available in Europe. Their arrival is awaited with eager anticipation, but the results may prove to be disappointing. The products may not be as side-effect free as they first seem.

    ii) The use of opioid drugs for the management of chronic non-malignant pain is fraught with difficulties, some real and some perceived. Morphine itself has tended not to be prescribed for chronic pain, because of a fear or stigma concerning Morphine. Physicians may fear dependence, tolerance and side-effects. There is a wide difference of opinion, which is still to be resolved; however, some patients can have their pain adequately controlled with opioids, without an unacceptable level of addiction problems. The potential risk of addiction remains a very real problem for a minority. Also, a significant number of patients with chronic pain complain of bothersome side-effects from medication. Mobility and distress must be monitored and benefits must accrue in both these parameters, as well as in reduction of pain.

    iii) In the UK and in the USA, traditionally most patients with chronic pain receive an opioid derivative such as Codeine, Dihydrocodeine or Dextropropoxyphene. In the past Pentazocine and Buprenorphine enjoyed a passing vogue but are now little used. Pentazocine proved to have unacceptable side-effects, and Buprenorphine, originally thought to be non-addictive, was shown to have addictive potential and since being classified as a controlled drug has enjoyed little popularity. Nefopam has limited efficacy and popularity, and Meptazinol is short-acting, and often associated with an unacceptable level of side-effects.

    Recent work suggests that Codeine and Dihydrocodeine are merely pro drugs for Morphine, and exert their action through metabolism to this compound. Given that a significant number of the population do not have the metabolic pathway to facilitate this, it is not surprising that there is a significant failure rate to produce any analgesia at all and that patients getting analgesia seem to get limited relief-hence possibly the popularity of these preparations being compounded with Paracetamol. There is good evidence that in some patients, much of the analgesic effect in these combined preparations lies with the Paracetamol itself, whilst many of the side-effects lie with the opioid.

    v) Tramadol hydrochloride is an orally active, clinically effective, centrally-acting analgesic. It can produce analgesia that has been compared to Codeine or Dextropropoxyphene. It has been used in post-surgical pain, obstetric pain, cancer pain and chronic pain of mechanical and neurogenic origin. Analgesic tolerance is not a significant problem, and psychological dependence and euphoric effects are minimal. There are a significant number of patients in the chronic group who develop side-effects, but many of those who tolerate the drug get useful benefit in pain reduction. This slow-release formulation is an appropriate vehicle for chronic pain management.

    Tramadol has an affinity, albeit relatively weak, for mu opioid receptors. It is also a neuronal uptake inhibitor. The monoamine neurotransmitters 5HT (Serotonin) and Noradrenaline (NA) are involved in the inhibition of spinal cord dorsal horn neurone responses to painful stimulation (i.e. closing the gate). Analgesia can result from activating the pain inhibitory pathways originating from higher CNS levels, and containing these neurotransmitters. Tramadol inhibits the uptake of 5HT and Noradrenaline but not Adenosine, Cyclic AMP, Dopamine, or Gaba.

    Metanalysis by Moore and McQuay indicates an appropriate dose response curve for Tramadol, and suggests a reduced number needed to treat to show therapeutic efficacy as compared with Codeine, in doses of 75 to 150 mg. Nausea, vomiting and dizziness are greater than with Codeine, somnolence about the same and constipation much less. In the chronic pain situation nausea and vomiting are attenuated with usage, as is somnolence for both drugs, but constipation remains a particular problem with Codeine and Dihydrocodeine, and less of a problem with Tramadol.

    Side-effects from Tramadol can be minimised by starting with a low dose and increasing gradually. There is evidence that this reduces the side-effects and improves tolerance. According to need, it can be started in a low dose of 50 mg daily or twice a day, and gradually titrated to reach 50 mg three times a day by day 3. Once a patient is established on a therapeutic dose, they can be put on the slow-release formulation to provide round-the-clock analgesia.

    B. PSYCHOACTIVE DRUGS.

    i) Anticonvulsants are well acknowledged as being effective in the management of shooting pain, for example: trigeminal neuralgia and the shooting element of neurogenic pain, such as post-herpetic neuralgia, diabetic neuropathy and similar conditions. Carbamazepine appears to be the most effective drug although there is a higher incidence of side-effects than with Sodium Valproate. Recently Gabapentin and Lamotrigine are enjoying popularity, either as “add on” drugs, or as sole agents. Further drug development of these types of agents might produce useful efficacy in the future.

    ii) Tricyclic antidepressants are one of the most commonly used analgesics in pain clinics. This is not for the specific antidepressant action, but is more associated with the activation of pain inhibitory pathways. This appears to be less of a feature with the tetracyclic agents, and has meant that their usage in chronic pain has as yet remained unproven. This is of course is disappointing as the side-effect profile is significantly better. The sedative effect of Amitriptyline can be harnessed to good usage by giving the tablet one or two hours before retiring, and it should not be used during the day.

    ANALGESIC PAIN MANAGEMENT

    In general, patients with pain can be given a trial of Paracetamol. An appropriate non-steroidal can be used if there is an inflammatory process, and continued if these are effective and if side-effects are minimal. The next optimal step in the analgesic ladder will be the use of agents like Tramadol, Dextropropoxyphene, or Dihydrocodeine, with long-acting preparations being ideal for chronic pain. At present, slow-release Tramadol would appear to be the most effective drug in chronic pain for this group of patients. If side-effects preclude its usage, one of the other agents can be considered.

    Finally a small group of patients might be suitable for the use of opioids themselves.

    In conjunction with this ladder, anticonvulsants and tricyclic antidepressants can be considered, for their specific and appropriate actions on shooting and burning pain, usually of neurogenic origin.

    Acute Pain

    Acute pain is the symptom of a larger disease process, and is usually nocioceptive in nature. This means that a noxious (unpleasant) event stimulates the intact nervous system to produce the sensation of pain. Examples of this noxious event include a surgical incision, labor pain, acute pancreatitis or a myocardial infarction.

    Acute pain can be somatic or visceral or neuropathic in origin. Somatic pain is sharp and well localized in nature, usually to an external site. Visceral pain tends to be dull and vaguely localized to a deep site, and is frequently associated with nausea. Acute pain is self-limiting, and resolves when the noxious stimulus ceases.

    Physiological and psychological responses to acute pain are directed toward escape from the painful situation. Acute pain usually triggers a neuroendocrine stress response, which is proportional to the intensity of the pain. This is a variant of the fight-or-flight response. Catecholamines are released, increasing heart rate, blood pressure, and systemic vascular resistance. Other effects of this catecholamine release may include urinary retention, ileus, stress ulcers, increased work of breathing, nausea, and constipation.

    The predominant emotional response to acute pain is anxiety, although anger toward caretakers may also be expressed. These emotional responses indicate that the patient believes the pain to be temporary and “fixable”, and represent an attempt to escape from the painful stimulus.

    Acute pain usually responds well to non-steroidal pain relievers and/or narcotics. Frequently, neural blockade can effectively relieve acute pain and de-
    crease the likelihood of developing a chronic pain syndrome.