A Lady with Renal Stones

A lady with renal stones

Dr KC Lo, Dr KY Lo, Dr SK Mak KWH History

53/F NSND, NKDA Good past health Complained of bilateral loin pain for few years No urinary symptoms/UTIs No haematuria Not on regular medications/vitamins No significant family history History

Attended private practitioner in Feb, 2006: Blood test :

Na/K 143/3.9 Ur/Cr 7.3/101 LFT N Urine test : RBC numerous/HPF

WBC 5-8/HPF CXR unremarkable Given analgesics History

Still on-and-off bilateral loin and lower chest pain Seek advice from Private Hospital: Blood test: WBC 3.2 Hb 12.9 Plt 139 Na/K 146/ 3.0 Ur/Cr 6.3/108 Ca2+/PO4 2.11/1.39 LFT unremarkable Urine test : RBC 6-8/HPF, WBC 0-1/HPF no cast KUB: bilateral renal stones (as told by patient) History

ESWL done to right renal stone in 5/06, planned to have ESWL to left stone later

But she then defaulted FU History

This time admitted to our surgical ward complaining of similar bilateral lower chest wall pain (for six months) Had vomiting of undigested food 8 times per day for 1 day, no diarrhoea No fever Recent intake of herbs one week ago Physical exam

BP 156/77 P 68 afebrile Hydration normal Chest, CVS unremarkable Local tenderness over bilateral lower chest wall Abdomen soft, mild epigastric tenderness, no rebound and guarding

KUB

Multiple tiny calcific densities projecting in bilateral renal areas with apparent distribution of the renal medulla bilateral medullary nephrocalcinosis CT Scan 1 yr ago in private CT Scan 1 yr ago in private Investigations

WBC 3.1 HB 13.1 Plt 137 Na 137 K 2.3 Cl 112 Ur 4.7 Cr 99 Ca 2.18 PO4 0.5 LFT normal, serum albumin 43 ABG : pH 7.28 pCO2 4.4 HCO3 15.3 BE -10.2 MSU G –ve A trace RBC 1-4/HPF C/ST no growth

What next? Anion gap

Na – Cl – HCO3 = 137 – 112 – 15.3 = 10

Normal anion gap metabolic acidosis

Expected pCO2 = 0.1333 X (1.5(15.3)+8[ ± 2]) = 3.0-4.4 kPa

What next? Urine anion gap

Urine Na 42 K 17.5 Cl 45

Urine anion gap = Na + K – Cl = 14.5 What other lab data would you like to know?

Urine pH 7.0

Dx : distal renal tubular acidosis Investigations

PTH 1.2 pmol/L (N 1.6 -6.9 pmol/L) 24hr Ur TP 1.23g/d, CrCl 42ml/min

24hr Ur Ca 2.64mmol/d (N: 2.5 -7.5 mmol/d )

UPE and SPE : no monoclonal band detected

Serum Vitamin D level : 25 OH 13.4 ug/L (N >10) Investigations

USG abdomen : Bilateral renal medulla appear hyperechoic with shadowing seen, consistent with medullary nephrocalcinosis, no hydronephrosis No splenomegaly Investigations

Skeletal survey : No Looser ’s zone Reduced bone density in the lumbrosacral spine with loss of lumbar lordosis Herbal medicine formula Investigations

The herbal formula were sent to Toxicology Reference laboratory for analysis those ingredients ( 桑寄生,泰艽,川芎,白芍, 太子參, 三七, 薑黃, 元胡, 鬱金,佛手,香附,黃著, 甘草,雞血滕,大黃, 火麻仁, 枳實, 厚樸,甜杏仁,續斷, 絡石藤) are not known to cause metabolic acidosis and hypokalaemia In summary

The patient has distal renal tubular acidosis (type 1) with bilateral medullary nephrocalcinosis

What is the cause ? Major cause of Type I RTA in adult

Primary Secondary Sjogren ’s Syndrome Idiopathic, sporadic Rheumatoid arthritis Familial SLE AD/AR Hypercalciuria Hyperglobulinaemia Cirrhosis Sickle cell anaemia Amphotericin B Lithium carbonate Ifosfamide Renal transplantation Obstructive uropathy On further questioning

She complained of dry eyes for many years and took regular eye drops bought over the counter

Difficulties in swallowing biscuits or bread for one year

Schirmer’s test +ve Further Investigations

ANA 1280 Anti-ds DNA <10 Ig G 16.7 (N 7.4 – 15.5) Ig A 5.10 (N 0.82 – 4.53) Ig M 0.98 (N 0.46-3.04) C3 0.65 (N 0.79-1.52) C4 0.31 (N 0.16-0.38) RF +ve TFT normal

BMA and trephine : no malignancy Anti-ENA screen

Anti-Ro (SS-A) +ve Anti-La (SS-B) –ve Anti-RNP –ve Anti-SM –ve Anti-Scl-70 –ve Anti -Jo-1 –ve Anti-other -ve Progress

Ophthamologist : moderate dry eyes Artificial eyedrops and ointment Progress

She was treated with iv potassium supplement and then Put on Potassium citrate 2g bd Sodium bicarbonate 900mg tds In summary

The patient has

distal renal tubular acidosis (type 1) with bilateral medullary nephrocalcinosis due to Sjogren ’s syndrome Discussion

Nephrocalcinosis/nephrolithiasis in distal renal tubular acidosis Renal disease in Sjogren ’s Syndrome Aggressive treatment ? Alkali therapy in dRTA Nephrocalcinosis/ Nepholithiasis Nephrocalcinosis

Deposition of calcium within the renal parenchyma Classify according to the anatomic area involved : Medullary nephrocalcinosis Cortical nephrocalcinosis Common cause of medullary nephrocalcinosis

Hyperparathyoridism Nephrotoxic drug Distal RTA (amphotericin B, outdated tetracycline) Bartter syndrome Primary hyperoxaluria Bone metastasis Renal tuberculosis Chronic pyelonephritis Sarcoidosis Cushing syndrome Sickle cell disease Hypo/hyperthyroidism Vitamin D excess Idiopathic hypercalcaemia Medullary sponge kidney Common cause of cortical nephrocalcinosis

Acute cortical necrosis Alport syndrome Chronic glomerulonephritis Chronic hypercalcaemic states Ethylene glycol poisoning Oxalosis Rejected renal transplant Sickle cell disease Workup in nephrocalcinosis

Blood Na, K, Cl, blood gas analysis PTH (in case of increase calcium levels) Vitamin D and metabolites Urinalysis Urine pH (measurement after each voiding, minimum 4x/day) 24hour urine (2 collections)

Volume, urine pH, specific weight, Ca2+, PO4, oxalate, uric acid, citrate, magnesium Nephrolithiasis in renal tubular acidosis

Frequently seen in dRTA but rare in pRTA Nephrolithiasis in distal renal tubular acidosis

Hypercalciuria Persistent acidaemia was buffered by bone calcium carbonate release of calcium in urine Increase PTH increase release of bone calcium Increase circulating H+ ion concentration reduce negative charges on serum proteins more free form Ca2+ circulates more for glomerular filtration Acidosis induced inhibition of tubular calcium reasborption (unknown mechanism) Nephrolithiasis in distal renal tubular acidosis

persistently high urine pH favors the precipitation of calcium phosphate Hypocitraturia

acidemia enhances proximal citrate reabsorption and its metabolism

Not related to low serum citrate concentration or hypokalemia Citrate is a potent stone formation inhibitor both by forming a soluble complex with calcium and by inhibiting stone growth by agglomeration of calcium crystals

Often improves only modestly with alkali therapy Nephrolithiasis in distal renal tubular acidosis

Amplify the acidification dysfunction

By impairing the transfer of NH 3 from the LH to the collecting duct Recurrent pyelonephritis common Can be difficult to treat Renal disease in Sjogren ’s Syndrome

Prevalence varied widely, ranging from 2 to 67 % Renal disease in Sjogren ’s Syndrome

20 out of 471 (4.2%) patient showed overt renal involvement : Proteinuria > 500 mg /d Serum creatinine > 140 umol/L Active urinary sediments CrCl < 50ml/min Evidence of distal RTA recurrent renal colic with imaging findings of urolithiasis or nephrocalcinosiasis Fanconi syndrome without any other identifiable cause 18 patients Bx done out of 20 such patients

Clinically significant and biopsy-documented renal involvment in primary Sjogren ’s syndrome Goules : Medicine (Baltimore), Vol 79(4) July, 2000. 241-249 Renal disease in Sjogren ’s Syndrome -- Histopathology

Chronic interstitial nephritis (10/18)

Presence of small lymphocytes, plasma cells and monocytes in the interstitium combined with tubular atrophy and fibrosis

Clinical presentation : RTA type I with/without acidaemia Impairment in urine concentrating ability Fanconi syndrome

Glomerulonephritis (9/18) Mesangial proliferative (5/9) Proliferation of mesangial cells and matrix Clinical presentation : mild haematuria, proteinuria, hypertension Membranoproliferative (4/9) Diffuse proliferation of mesangial cells and infiltration of glomeruli by macrophages, increased mesangial matrix, thickening and reduplication of GBM Clinical presentation : Variable combinations of nephritic and nephrotic syndrome with active urine sediment Moderate proteinuria Acute decline in GFR

Clinically significant and biopsy-documented renal involvment in primary Sjogren ’s syndrome Goules : Medicine (Baltimore), Vol 79(4) July, 2000. 241-249 Renal Outcome over a 15 yr FU

Glomerulonephritis (8 patients): 2 progressed to ESRF Mixed monoclonal cryoglobulinaemia more frequently observed (p = 0.023) Interstitial Nephritis (10 patients): 4 patients had mild to moderate impairment in renal function, but no evidence of deterioration during follow up, no RRT required younger at disease onset (36.8 +/- 11.9 vs 46 +/- 7.07) ( p = 0.063) developed earlier during the course of disease (2.2 +/- 3.2 vs 8 +/- 5.5yr) (p = 0.001)

Clinically significant and biopsy-documented renal involvment in primary Sjogren ’s syndrome Goules : Medicine (Baltimore), Vol 79(4) July, 2000. 241-249 Distal Renal Tubular Acidosis in Sjogren ’s syndrome

mechanism incompletely understood immunocytochemical analysis complete absence of the H-ATPase pump in the intercalated cells in the collecting tubules that is largely responsible for distal proton secretion but mechanism of immune injury unknown high titers of autoantibody directed against carbonic anhydrase II resulting in fewer hydrogen ions generated within the cell available for secretion

Autoantibodies against carbonic anhydrase II are increased in tubular acidosis assoicated with Sjogren Syndrome AJM (2005) 118, 181-184 18 patients with biopsy-proven Renal disease in Sjogren ’s Syndrome

Treatment for Glomerulonephritis (10) Serum creatinine ( 70 – 548 umol/L)

6 received MP and iv pulse/oral cyclophosphomide 1 received MP and azathioprine

2 received MP alone 1 no treatment

Clinically significant and biopsy-documented renal involvment in primary Sjogren ’s syndrome Goules : Medicine (Baltimore), Vol 79(4) July, 2000. 241-249 Pulse high dose corticosteroid for severe interstitial nephritis in primary Sjogren ’s Syndrome

Case report, 22/F metabolic acidosis Cr 125 umol/L (+ “subsequent progressive renal insufficiency ”) CrCl 50ml/min Renal biopsy showed severe interstitial nephritis

iv MP 1g/day x 3d, then oral MP 24mg/day for 6 months

Remission of the renal involvement in patient with primary Sjogren ’s Syndrome after pulse high-dose corticosteroid infusion therapy Clin Rheumatol (2001) 20:225-228 Pulse high dose corticosteroid for severe interstitial nephritis in primary Sjogren ’s Syndrome

After 6 months of therapy dramatic improvement in sicca symptoms Hb 8.6 12 Normalized Cr level Metabolic acidosis corrected without alkali supplement Repeat biopsy showed markedly decrease in inflammatory cell infiltration normal tubular pathology in absence of obvious interstitium fibrosis Corticosteroids gradually tailed down

Remission of the renal involvement in patient with primary Sjogren ’s Syndrome after pulse high-dose corticosteroid infusion therapy Clin Rheumatol (2001) 20:225-228

Rituximab for dRTA ?

Case report, 55/F with pSS and dRTA without lymphoma

No proteinuria

Refractory and severe dry mouth with oral erosions and ulcer Treated with rituximab iv 375mg/m2 weekly x 4 doses

oral ulcers healed Repeat labial biopsy showed significantly less infiltration with lymphocytes

No change in dose of alkali supplement

Successful treatment of a patient with primary Sjogren ’s Syndrome with Rituximab Clin Rheumatol (2006) 25: 891 - 894 Urine alkalinisation

Aim to achieve a relatively normal plasma bicarbonate concentration (22 to 24 mEq/L) Usu 1-2 mEq alkali per kg of BW Up-titrate based on 24hour urine excretion of citrate Urine pH should be monitored because calcium phosphate precipitation occurs if pH > 7.0 Urine alkalinisation/treatment for hypocitraturia

Potassium citrate citrate is rapidly metabolized to bicarbonate more palatable than bicarbonate solutions concurrent hypokalemia can also be corrected Reduce hypercalciuria Citrate – stone formation inhibitor reduces the supersaturation of calcium oxalate by binding to calcium direct interference with calcium oxalate crystallisation

A comparsion of the effects of potassium citrate and sodium bicarbonate in the alkalization of urine in homozygous cystinuria Urol Res (2001) 29: 295 - 302 Urine alkalinisation/treatment for hypocitraturia

Sodium bicarbonate Unpalatable and causes abdominal bloating Additional sodium load may exacerbate hypercalciuria, since calcium reabsorption passively follows that of sodium in the proximal tubule and loop of Henle Raises sodium urate saturation 3.9 mEq/325 mg tablet

A comparsion of the effects of potassium citrate and sodium bicarbonate in the alkalization of urine in homozygous cystinuria Urol Res (2001) 29: 295 - 302 pH-dependent urinary excretion of drugs

Alkali therapy in RTA results in intense alkalinity of urine Pseudoephedrine (cough mixture) Cinchona alkaloids Quinidine Quinine Salicylates High pK (>8): Decreased excretion of drug Raised blood levels Thank You Role of renal biopsy in Sjogren ’s Syndrome

Renal biopsy is probably not necessary in patient present with clinical and laboratory findings suggestive of IN, and the prognosis of these patient is good

Clinically significant and biopsy-documented renal involvment in primary Sjogren ’s syndrome Goules : Medicine (Baltimore), Vol 79(4) July, 2000. 241-249

Serum Anion Gap

Na – Cl – HCO3 primarily determined by the negative charges on the plasma proteins, particularly albumin. expected normal values for the AG must be adjusted downward in patients with hypoalbuminemia, with the AG falling by about 2.5 mEq/L for every 1 g/dL (10 g/L) reduction in the plasma albumin concentration Normal 7-13 mEq/L Urine Anion Gap

Urine (Na + K – Cl) difference is comprised of ammonium (NH4+) type 1 RTA, the urine AG is positive, because the defect in distal acidification results in low urine NH4+ levels In patients with a normal anion gap metabolic acidosis and hypokalemia due to diarrhea, the urine AG is negative because urine ammonium excretion rises appropriately in response to the acidosis

Sodium versus potassium There are several reasons for preferring alkaline potassium salts to sodium salts. Monosodium urate is considerably less soluble than monopotassium urate. Total urate solubility is therefore lower when the urinary sodium concentration is high.[ 4] Furthermore, monosodium urate can cause epitaxial growth of calcium oxalate, and the potassium salt does not. [ 10 and 11 ] Potassium citrate may actually decrease urinary calcium, [ 12 ] and sodium citrate may increase calcium excretion. Hence, sodium alkalinizing salts are much more likely to facilitate calcium stone formation and are marginally less likely to dissolve uric acid. Furthermore, many patients with uric acid stones are older, and a sodium load may aggravate coexisting hypertension or congestive heart failure. Sodium bicarbonate given alone can cause urinary potassium losses and lead to hypokalemia. On the other hand, if the patient has significant renal dysfunction, potassium salts can be dangerous. They have a peculiar taste, and some patients get a queasy feeling when they take potassium citrate alone. Wax matrix potassium citrate tablets avoid the upper gastrointestinal symptoms but six or eight 10-mEq tablets may be needed. They also provide less of a pulse effect, which can be important for uric acid stone dissolution. Potassium salts tend to increase diarrhea more than do sodium salts. If the cause of the patient ’s uric acid stones is gastrointestinal loss of base, potassium may make the situation worse. Hence, despite the theoretical reasons for preferring potassium salts, it is often appropriate to give some of the base as sodium !!!

Bicarbonate fraction excretion Ammonium chloride loading test Lasix test

Quote references

Renal tubular acidosis Renal role in acid-base balance

Reabsorption of bicarbonate predominantly (approx 85 to 90 %) occurs in the proximal tubules primarily by Na-H exchange 10% is reabsorbed in the distal nephron primarily via hydrogen secretion by a proton pump (H-ATPase) Under normal conditions, virtually no bicarbonate is present in the final urine Acid excretion distal tubule Renal tubular acidosis

Type 1 (distal) impaired distal acidification Type 2 (proximal) a reduction in proximal bicarbonate reabsorptive capacity that leads to bicarbonate wasting in the urine until the plasma bicarbonate concentration has fallen to a level low enough to allow all of the filtered bicarbonate to be reabsorbed Type 3 previously describe transient and severe form of type 1 RTA in infants, now most often applied to a rare autosomal recessive syndrome (resulting from carbonic anhydrase II deficiency) with features of both type 1 & type 2 RTA Type 4 decreased aldosterone secretion or aldosterone resistance Type I RTA Type 2 RTA Type 4 RTA

Primary Impaired distal Reduced proximal Decreased defect acidication bicarbonate aldosterone reabsorption secretion or effect

Plasma Variable, may < Usu 12 – 20 meq/L > 17meq/L bicarbonate 10meq/L

Urine pH > 5.3 Variable, > 5.3 if Usu < 5.3 above bicarbonate reabsorptive threshold

Plasma K Usu reduced but Reduced, made increased hyperkalaemic worse by form exit; bicarbonaturia hypokalaemia induced by alkali largely correct therapy with alkali Distal RTA (type I)

Hyperchloremic acidosis with inappropriately high urine pH (>5.5 in presence of acidosis) Associated with hypercalciuria due to effects of chronic acidosis on both bone reabsorption and renal tubular reabsorption of calcium Hypercalciuria development of nephrolithiasis and nephrocalcinosis Distal RTA (type I)

Hypokalamia Potassium wasting with a proton pump defect is in part related to the reduction in distal hydrogen secretion potassium secretion must be enhanced to maintain electroneutrality as sodium is reabsorbed Pathogenetic mechanism in dRTA

Decrease acidification in collecting tubules (Decrease H+ secretion) 1) defect in H+ - ATPase pump in intercalated cells 2) voltage-dependent defect :

Decrease Na + reasborption by principal cells decrease electrical gradient for secretion of H+ and K+ hyperkalaemic form of dRTA 3) gradient defect (toxin)

Increase membrane permeability backdiffusion of H+ ions

Sj ögren's syndrome Sj ögren's syndrome

typically associate with a lymphocytic and plasmacytic infiltrate in the salivary, parotid, and lacrimal glands, leading to a sicca syndrome can also affect nonexocrine organs, including the kidneys, producing an interstitial nephritis and defects in tubular function Revised international classification criteria for Sj ögren's syndrome

I. Ocular symptoms: a positive response to at least 1 of the following questions: 1. Have you had daily, persistent, troublesome dry eyes for more than 3 months ? 2. Do you have a recurrent sensation of sand or gravel in the eyes? 3. Do you use tear substitutes more than 3 times a day?

II. Oral symptoms: a positive response to at least 1 of the following questions: 1. Have you had a daily feeling of dry mouth for more than 3 months? 2. Have you had recurrently or persistently swollen salivary glands as an adult? 3. Do you frequently drink liquids to aid in swallowing dry food? Revised international classification criteria for Sj ögren's syndrome

III. Ocular signs-that is, objective evidence of ocular involvement defined as a positive result for at least 1 of the following 2 tests: 1. Schirmer's test, performed without anaesthesia (5 mm in 5 minutes) 2. Rose bengal score or other ocular dye score (4 according to van Bijsterveld's scoring system) Schirmer ’s test

A small piece of sterile filter paper is placed in the lateral third of the lower eyelid the extent of wetting in a given time is measured Wetting of less than 5 mm in five minutes is considered abnormal Use of topical anesthesia and blotting of the tear reservoir prior to the test may improve accuracy as a measure of basal tear production The amount of wetting is typically symmetrical Rose Bengal Score

To measure the end organ damage to conjunctival and corneal epithelial cells by Rose Bengal stain (which stains areas of devitalized tissue) Method : 10 µL of 1 percent Rose Bengal is instilled into the inferior fornix of the unanesthetized eye, the patient blinks twice, then the extent of staining of conjunctiva and cornea is scored

Revised international classification criteria for Sj ögren's syndrome

IV. Histopathology: Biopsy in minor salivary glands (obtained through normal-appearing mucosa) focal lymphocytic sialoadenitis focus score 1, defined as a number of lymphocytic foci (which are adjacent to normal-appearing mucous acini and contain more than 50 lymphocytes) per 4 square mm of glandular tissue Revised international classification criteria for Sj ögren's syndrome

V. Salivary gland involvement: objective evidence of salivary gland involvement defined by a positive result for at least one of the following diagnostic tests: 1. Unstimulated whole salivary flow (1.5 ml in 15 min) 2. Parotid sialography showing the presence of diffuse sialectasias (punctate, cavitary or destructive pattern), without evidence of obstruction in the major ducts 3. Salivary scintigraphy showing delayed uptake, reduced concentration and/or delayed excretion of tracer VI. Autoantibodies: presence in the serum of the following autoantibodies: 1. Antibodies to Ro(SSA) or La(SSB) antigens, or both Exclusion criteria

if one of the following disorders is present : Prior head and/or neck irradiation Infection with hepatitis C virus Acquired immunodeficiency disease (AIDS) Pre-existing lymphoma Sarcoidosis Graft versus host disease Recent use of drugs with anticholinergic propertie Rules for classification Primary Sj ögren's syndrome — For patients with no associated connective tissue or autoimmune disease (eg, RA, SLE) and no exclusionary diagnoses, a classification of primary SS is made according to the consensus rules in one of the three following ways : 1. The patient has either a positive salivary gland biopsy result or autoantibodies, and satisfies a total of 4 of the six items (sensitivity 97%, specificity 90%) . 2. Alternatively, the patient satisfies three of the four objective items (ocular signs, biopsy, salivary gland involvement, or autoantibodies). (sensitivity 84%, specificity 95%) 3. classification tree with sensitivity of 96% and specificity of 94% can be used to determine whether or not patients are classified as having primary SS

Rules for classification

Secondary Sj ögren's syndrome — A classification of secondary SS is made if a "well defined" connective tissue disease is present and at least 1 symptom item (indicative of ocular or oral dryness) and any 2 of 3 objective items exclusive of autoantibodies (ie, ocular signs, biopsy, or tests of salivary gland involvement other than biopsy) are present