Primary hyperoxaluria and renal hypercalciuria

1. Primary Hyperoxaluria and renal
hypercalciuria
Dr Prateek Laddha
Senior Resident Urology

2. Definition of Hyperoxaluria
 The normal upper level of urinary oxalate excretion is 40 mg (440 µmol)
in 24 hours.
 Men have a slightly higher normal value (43 mg/d in men vs 32 mg/d in
women), but this is primarily due to larger body habitus and larger
average meal size rather than to any real intrinsic metabolic difference.
 Stone formation risk probably depends more on absolute total oxalate
excretion and concentration than on arbitrary normal values.

3.  Reflecting these normal values, the usual definition of hyperoxaluria is
urinary oxalate excretion that exceeds 40 mg/day. The 4 main types of
hyperoxaluria are the following[1, 2] :
 Primary hyperoxaluria (types, I, II and III)
 Enteric hyperoxaluria
 Dietary hyperoxaluria
 Idiopathic or mild hyperoxaluria

4. Oxalate Production and Function
 Oxalate is an organic salt with the chemical formula of C2 04.
 At physiological pH levels, oxalate forms a soluble salt with sodium and
potassium;
 however, when combined with calcium, it produces an insoluble product
termed calcium oxalate, which is the most common chemical compound
found in kidney stones.

5.  Oxalate is absorbed primarily from the colon, but it can be absorbed
directly from anywhere in the intestinal tract.
 In addition, oxalate is created from endogenous sources in the liver as
part of glycolate metabolism. In the kidney, oxalate is secreted in the
proximal tubule via 2 separate carriers involving sodium and chloride
exchange.

6. Oxalate balance on a typical western diet
10%
30%
Diet
100 mg
Stool
90 mg
Glyoxylate Ascorbic
Acid
Endogenous
Production
24 mg (1 mg/hr)
Absorbed
10 mg
Renal Excretion
34 mg

7.  Oxalate is normally produced in plants, primarily in their leaves, nuts, fruit,
and bark.
 The amount of oxalate manufactured depends not only on the particular
variety of plant but also on the soil and water conditions in which it grows.
 In general, plants that are grown in fields with a high concentration of
ground water calcium have higher concentrations of oxalate.
 This is one reason why precisely calculating dietary oxalate is difficult.

8.  Oxalate content within the same plant species can vary widely. For example, potatoes contain
oxalate levels of 5.5-30 mg per 100 g, broccoli has levels of 0.3-13 mg per 100 g, and wheat bran
has levels of 58-524 mg per 100 g.
 Plants use oxalate as a calcium sink. Any excess calcium absorbed by the plant from ground water is
extracted from the plant’s tissue fluid by the oxalate in the leaves, fruits, nuts, or bark. Eventually,
the plant sheds these structures. When humans eat these plant products, they also ingest a variable
quantity of oxalate. Food products from animal sources have virtually no oxalate content.

9.  Oxalate is involved in various metabolic and homeostatic mechanisms in fungi and bacteria and
may play an important role in various aspects of animal metabolism, including mitochondrial
activity regulation, thyroid function, gluconeogenesis, and glycolysis.
 Interestingly, oxalate was first discovered in animals when sheep became ill after eating vegetation
later found to have high oxalate content.

10.  In humans, however, oxalate seems to have no substantially beneficial role and acts as a metabolic
end-product, much like uric acid.
 If not for oxalate’s high affinity for calcium and the low solubility of calcium oxalate, oxalate and
oxalate metabolism would be of little interest.
 Urinary oxalate is the single strongest chemical promoter of kidney stone formation.
 Ounce for ounce, it is roughly 15-20 times more potent than excess urinary calcium.

11.  Daily oxalate intake in humans is usually 80-120 mg/d; it can range from 44-350 mg/d in individuals
who eat a typical Western diet. The solubility of oxalate at body temperature is only approximately
5 mg/L at a pH of 7.0.
 Among persons with stones, urinary oxalate levels tend to be significantly higher in summer than in
winter.
 This may be due to the increased consumption of seasonal foods naturally high in oxalate (see the
image below). In addition, the average mean urinary oxalate excretion in persons with calcium
stones tends to be higher than in individuals without calcium stones.

13. Pathophysiology and Etiology
High levels of oxalate in the system can produce various health problems, particularly kidney stone
formation.
The 4 main types of hyperoxaluria—
 primary hyperoxaluria (types I and II),
 enteric hyperoxaluria,
 dietary hyperoxaluria, and
 idiopathic or mild hyperoxaluria—are the results of different pathophysiologic processes (see
below).

14. Primary hyperoxaluria
 This rare form of hyperoxaluria is due exclusively to a genetic defect that causes a loss of specific
enzymatic activity.
 With the normal metabolic pathway blocked, the alternative pathway that leads to oxalate
production as an end-product of glycolate metabolism becomes extremely active, resulting in
extremely high oxalate production.

15. Type I hyperoxaluria
 Type I hyperoxaluria is more common than type II:
 it occurs in 1 per 120,000 live births
 Autosomal recessive disorder
 In primary hyperoxaluria type I, the missing enzyme is alanine-glyoxylate aminotransferase (ie,
the AGTgene)
 normally found only in the hepatic peroxisomes.
 This enzyme is necessary to detoxify glyoxylate.
 When alanine-glyoxylate aminotransferase is lacking, oxalate production soars.

16.  Pyridoxine (vitamin B-6) is a cofactor in this chemical pathway, which normally converts glyoxylic
acid (C2 H2 O3) to glycine.
 When the pathway is blocked because of a deficiency or absence of this enzyme, the result is high
levels of glycolic and oxalic acid, which readily convert to oxalate.
 Oxalate is then excreted in the urine, which leads to nephrocalcinosis and the eventual
development of end-stage renal failure, usually in childhood.

17. Type II hyperoxaluria
 Type II hyperoxaluria is much less common than type I.
 In primary hyperoxaluria type II, the missing enzyme is D-glyceric dehydrogenase, which can be
detected in leukocyte preparations.
 This deficiency promotes the conversion of glyoxylate to oxalate.
 The 2 types of primary hyperoxaluria result in approximately the same degree of hyperoxaluria.
 However, end-stage renal disease is slightly less common in patients with type II primary
hyperoxaluria. Pyridoxine is generally not effective in patients with type II primary hyperoxaluria.

18. III PRIMARY HYPEROXALURIA
 Recently, a type III primary hyperoxaluria, due to mutations in the HOGA1(formerly DHDPSL)
gene has been described.
 This may result in an increase in mitochondrial 4-hydroxy-2-oxoglutarate aldolase activity and
excess oxalate production.
 Type III has been reported as a possible cause in patients with idiopathic calcium oxalate stones.
 However, no end-stage renal disease has been reported, suggesting that this type may be a
milder form of primary hyperoxaluria.

20. Prognosis
 The consequences of hyperoxaluria, like those of all forms of stone
disease, are related to stone formation and subsequent damage to the
urinary tract.
 These may include pain, renal obstruction, urosepsis, renal insufficiency,
renal failure, and even death. Primary hyperoxaluria in particular is
associated with the most serious health consequences.
 Approximately half of patients diagnosed with this disorder develop end-
stage renal disease, and the mortality rate, particularly in infants, is high
(>50%).

21.  Without treatment, the prognosis for these patients is poor. Renal failure
develops in 50% of patients with primary hyperoxaluria by age 15 years
and in 80% by age 30 years.
 Normal dialysis for uremia cannot remove enough serum oxalate to
protect the kidneys and other organs from widespread calcium oxalate
deposition (ie, oxalosis) and calcium oxalate stone production.
 The prognosis of primary hyperoxaluria depends on early treatment and
management of hyperoxaluria and associated renal deterioration.

22.  If medical treatment cannot help the patient maintain a normal oxalate
level, nephrocalcinosis may develop, with subsequent renal failure. In this
situation, combined liver-renal transplantation is necessary for cure.
 The prognosis of enteric and mild hyperoxaluria is favorable if medical
management and dietary modifications are followed. Periodic retesting
using 24-hour urine assessments should be performed regularly to
monitor compliance and treatment effectiveness.

23. CLINICAL MANIFESTATIONS
 The median age for presentation of initial symptoms related to
hyperoxaluria is 5 years. Oxalate deposition can occur in other organs
(eg, bones, joints, eyes, heart).
 In particular, bone tends to be the major repository of excess oxalate in
persons with primary hyperoxaluria.
 Bone oxalate levels are negligible in healthy individuals.
 Oxalate deposition in the skeleton tends to increase bone resorption and
to decrease osteoblast activity.

24.  Because symptoms occur relatively late and are associated with serious complications, all pediatric
patients who have stones should be screened for hyperoxaluria.
 Discovering this condition in siblings may allow earlier testing, detection, diagnosis, and preemptive
therapy.

25.  Urinary oxalate excretion is typically more than 100 mg/d in both types of primary
hyperoxaluria. A liver biopsy can be helpful in determining which type of enzyme defect
(alanine-glyoxylate aminotransferase or D-glyceric dehydrogenase) is present. Primary
hyperoxaluria may result in renal failure due to nephrocalcinosis.
 Enteric hyperoxaluria is characterized by very high urinary oxalate levels (usually 80 mg/d
or more) and hypocalciuria, with urinary calcium excretion usually less than 100 mg/d.

26.  Other conditions associated with enteric hyperoxaluria include fat
malabsorption, steatorrhea, inflammatory bowel disease, pancreatic
insufficiency, biliary cirrhosis, and short-bowel syndrome.
 Urinary oxalate excretion in idiopathic or mild hyperoxaluria is usually 40-
60 mg/d. Most patients with relatively mild hyperoxaluria (approximately
40-60 mg/d) have dietary hyperoxaluria.

27. Urine Chemistry
 Obtain a 24-hour urine collection and include analysis for total creatinine (ie, to determine
adequacy of the collection) and other urinary chemistry components that can lead to stone
formation, such as oxalate, calcium, uric acid, sodium, phosphate, and total urinary volume.
 Include an analysis for inhibitors of stone formation, such as
 potassium,
 citrate, and
 magnesium.
 Assess total urine volume and pH to determine the contribution of dehydration or pH to the
tendency toward crystallization.

28.  All major urinary risk factors (eg, calcium, oxalate, citrate, uric acid, total volume, sodium, phosphate, magnesium)
should be periodically reassessed with 24-hour urine collection
 to monitor treatment efficacy,
 to identify new kidney stone metabolic risk factors, and
 to monitor patient compliance.
 Repeat testing every 2-3 months while various treatment plans are used until
 acceptable urinary chemistry levels are reached or
 maximum therapy has been instituted.
 Thereafter, retesting every 1-2 years depending on the clinical situation is usually sufficient.
 The overall success of any stone preventive therapy program depends on
 the individual patient’s compliance with long-term preventive therapy and
 the continuous maintenance of an adequate urinary volume.

29. imaging
 Computed Tomography
 Intravenous Pyelography
 Renal Ultrasound and KUB Radiography

30. General Principles of Treatment
 Treatment of hyperoxaluria depends somewhat
 on the underlying etiology and
 severity of the hyperoxaluria.
 Many of the treatments mentioned can be used in any case of hyperoxaluria, and they can be
combined for increased efficacy.

31.  Initial first-line therapies include
 a low-oxalate diet while maintaining adequate calcium intake,
 pyridoxine (B-6),
 increased fluids, and optimization of other calcium oxalate nephrolithiasis risk factors.
 Limit ingestion of vitamin C and
 cranberry juice products.
 Calcium supplements are the initial treatment of choice for enteric hyperoxaluria, along with a low-
fat diet, antidiarrheal therapy, and sufficient potassium citrate supplementation to maintain optimal
urinary citrate levels.
 Vitamin E can be safely added to any hyperoxaluria treatment regimen.

32.  When initial treatment is insufficient to adequately control excessive urinary oxalate excretion, add
orthophosphate supplementation, magnesium supplementation, or both.
 Both of these therapies can have adverse gastrointestinal effects; therefore, dosages should be
titrated to tolerability.
 Phosphates are preferred in patients with hypophosphatemia or a low level of urinary
pyrophosphate, while magnesium therapy is selected in patients with hypomagnesemia or
hypomagnesuria.

33.  Oxalate-binding agents such as calcium (preferred) or iron (if hypercalciuria is present) can be used.
A higher dose of pyridoxine, up to 400-500 mg/d in divided doses, may also be helpful.
 If further treatment is necessary, cholestyramine can be added. Pentosan polysulfate (Elmiron) can
be considered, although its actual effectiveness is unclear.
 Pushing fluids to increase urinary output to 3-4 L/d may be helpful. Other risk factors should be
further optimized.
 In cases of renal failure, intensive dialysis can be considered. Liver or combined liver-renal
transplantation should be considered in patients with primary hyperoxaluria.[35, 36]

34. Treatment of Primary Hyperoxaluria
 rPatients with primary hyperoxaluria usually present with a urinary oxalate level in excess of 100
mg/d. Early medical treatment is required to decrease the oxalate level and to prevent
deterioration of renal function. Early liver-kidney transplantation is often required for definitive
cure. However, the survival rates and organ survival rates in patients who undergo treatment for
type I hyperoxaluria are inferior to such rates in general transplant patients.[45, 46, 47]
 Dietary oxalate restrictions are of no substantial benefit in this type of hyperoxaluric disease.
Several medications have been useful.
 New and future treatment modalities under investigation include probiotic
supplementation,[48] chaperones and hepatocyte cell transplantation, and recombinant gene
therapy to replace the enzyme.[49]

35.  High-dose pyridoxine (vitamin B-6)
 Pyridoxine deficiency is known to increase urinary oxalate excretion. High-dose pyridoxine may
reduce the production of oxalate by enhancing the conversion of glyoxylate to glycine, thereby
reducing the substrate available for metabolism to oxalate.[4] A daily dose of 150-500 mg may be
required to sufficiently reduce the oxalate level. A normal urinary oxalate level (< 40 mg/d) can
achieved in some patients.[42]
 Treatment of pyridoxine-resistant primary hyperoxaluria frequently involves combinations of all
available therapies and may ultimately entail renal-liver transplantation.[50]

36.  Orthophosphate
 Orthophosphate, in combination with pyridoxine, has been used effectively in the treatment of
primary hyperoxaluria. Milliner et al and others have demonstrated long-term treatment benefits
with this combination.[51] The phosphate increases urinary pyrophosphate and complexes with
calcium, thus decreasing the urinary calcium level, while pyridoxine reduces urinary oxalate
excretion.
 Phosphate therapy should not be used in patients with renal failure.

37.  Magnesium
 Supplementation with magnesium in the form of magnesium hydroxide andmagnesium
been used. Magnesium can complex with oxalate in the intestinal tract, reducing the level of
available free oxalate and urinary calcium oxalate supersaturation. It does not directly affect the
increased endogenous production of oxalate.[22, 12]
 When used in combination with pyridoxine, significant reductions in urinary oxalate levels have
been noted.

38.  Increased urinary volume
 It is essential to increase urinary volume. Optimal 24-hour urinary volumes of 3-4 L/d may be
needed to ameliorate the effects of severe hyperoxaluria. Increasing urine volume usually requires
multiple nightly disruptions of sleep for extra water consumption.
 Thiazides have been shown to decrease urinary oxalate excretion somewhat, possibly by
intestinal oxalate transport.
 Other factors that can contribute to stone formation, such as urinary citrate and uric acid, need
be optimized.

39.  Glycosaminoglycans (pentosan polysulfate)
 Supplementation with glycosaminoglycans may help to reduce calcium oxalate crystallization and
stone formation by reducing crystal aggregation. It also may decrease intestinal oxalate transport
and urinary oxalate excretion.[52, 43, 44]

40.  Intensive dialysis
 Intensive dialysis is needed in patients with primary hyperoxaluria and significant renal failure to
serum oxalate levels and to reduce the body stores of oxalate. The standard dialysis regimen for simple
uremia is not adequate to remove sufficient oxalate to prevent stone formation or other systemic
of oxalosis in severe hyperoxaluric states associated with renal failure. Daily hemodialysis sessions are
required that last 6-8 hours per day, which is considerably more dialysis than the typical patient with
stage renal failure needs.[53]
 Removal of the native kidneys often is recommended at the time of renal transplantation because the
native kidneys often have significant damage and residual stones, which makes them particularly
susceptible to recurrent infections and obstruction.
 Experimental studies in animal models have suggested that intestinal transport systems for oxalate are
altered in chronic renal failure, in which the entire intestinal tract, but primarily the colon, can excrete
oxalate. If medications could stimulate this process in patients without end-stage renal failure, it could
prove to be a useful therapy for hyperoxaluria.

41.  Oxalobacter formigenes administration
 Recent studies have demonstrated that O formigenes administration can promote oxalate
into the intestinal lumen.[54]
 Gene therapy
 Ultimately, a gene therapy that could replace the missing enzymes without the need for surgery
would be the ideal treatment for this serious disorder.

42. Renal hypercalciuria

43.  Hypercalciuria, or excessive urinary calcium excretion, is the most common identifiable cause of calcium
kidney stone disease.
 Idiopathic hypercalciuria is diagnosed when clinical, laboratory, and radiographic investigations fail to
delineate an underlying cause of the condition.
 Secondary hypercalciuria occurs when a known process produces excessive urinary calcium.
 The following are the most common types of clinically significant hypercalciuria:
 Absorptive hypercalciuria
 Renal phosphate leak hypercalciuria (also known as absorptive hypercalciuria type III)
 Renal leak hypercalciuria
 Resorptive hypercalciuria - This is almost always caused by hyperparathyroidism

44. Renal leak hypercalciuria
 Renal leak hypercalciuria occurs in about 5-10% of calcium-stone formers and is characterized by
fasting hypercalciuria with secondary hyperparathyroidism but without hypercalcemia.
 Defect in calcium reabsorption from the renal tubule
 that causes an obligatory, excessive urinary calcium loss.
 This results in hypocalcemia, which causes an elevation in the serum PTH.
 This secondary hyperparathyroidism raises vitamin-D levels and increases intestinal calcium absorption.
 Essentially, this means that, even in cases of undeniable renal leak hypercalciuria, an element of
absorptive hypercalciuria can be present.

46.  The diagnosis is relatively easy. Any patient who fails to control their excessive urinary calcium on
dietary measures alone and who demonstrates relatively high serum PTH levels without
hypercalcemia or hypophosphatemia probably has renal leak hypercalciuria.
 The calcium/creatinine ratio tends to be high in renal leak hypercalciuria (>0.20), and the
occurrence of medullary sponge kidney is more likely than in other types of hypercalciuria.
 Renal leak hypercalciuria is generally not amenable to therapy with dietary calcium restrictions,
because of the obligatory calcium loss, which can easily lead to bone demineralization, especially if
oral calcium intake is restricted.

47. Renal Hypercalciuria
 The kidney filters approximately 270 mmol of calcium and must reabsorb more than 98% of it to
maintain calcium homeostasis (Bushinsky, 1998).
 Approximately 70% of calcium reabsorption occurs in the proximal tubule, with paracellular pathways
predominating (Frick and Bushinsky, 2003).
 In renal hypercalciuria, impaired renal tubular reabsorption of calcium results in elevated urinary
calcium levels leading to secondary hyperparathyroidism (Coe et al, 1973).
 Serum calcium levels remain normal because the renal loss of calcium is compensated by enhanced
intestinal absorption of calcium and bone resorption as a result of increased secretion of PTH and
enhanced synthesis of 1,25(OH)2D3.
 High fasting urinary calcium levels (>0.11 mg/dL glomerular filtration) with normal serum calcium
values are characteristic of renal hypercalciuria.
 The elevated fasting urinary calcium and serum PTH levels differentiate renal from absorptive
hypercalciuria.

48.  The actual cause of renal calcium leak is not known.
 However, insight into the abnormalities associated with renal hypercalciuria comes from studies of
several monogenetic disorders associated with hypercalciuria and nephrolithiasis (Gambaro et al, 2004;
Langman, 2004; Devuyst and Pirson, 2007; Ferraro et al, 2013a).
Dent disease (X-linked recessive nephrolithiasis)
 linked to defects in chloride channel-5 (ClC-5),
 located in the proximal renal tubule, the thick ascending limb of the loop of Henle, and the α-type
intercalated cells of the collecting ducts.
 Dent disease is characterized by hypercalciuria, proteinuria, nephrolithiasis, nephrocalcinosis, and
progressive renal failure.
 Although the exact mechanism by which loss of ClC-5 results in hypercalciuria is not well understood, it
may involve loss of PTH as part of the low-molecularweight proteinuria, leading to elevated calcitriol
levels (Reinhart et al, 1995; Nakazato et al, 1997).

49. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC)
 is caused by mutations in claudin-16 (also known as paracellin-1) and claudin-19, members of
claudin gene family of tight junction proteins that are involved in the voltage driven paracellular
reabsorption of magnesium and calcium in the thick ascending limb and distal convoluted tubule
(Simon et al, 1999; Konrad et al, 2006).
 FHHNC patients develop a characteristic triad of hypomagnesemia, hypercalciuria, and
nephrocalcinosis as a result of progressive magnesium and calcium wasting.
 Other claudin abnormalities have also been associated with nephrolithiasis.

50. Bartter syndrome
 Bartter syndrome encompasses a group of autosomal recessive disorders
 Dysfunction in the thick ascending limb of the loop of Henle
 Salt wasting and hypokalemic metabolic acidosis, with variable occurrence of hypercalciuria and
nephrolithiasis
 This disorder arises from a mutation in any of the genes encoding membrane proteins involved
in transepithelial sodium chloride transport across the thick limb of the loop of Henle
 Activating mutations in the gene encoding the CaSR have been associated with an autosomal
dominant form of hypocalcemia by which low serum PTH levels lead to reduced renal calcium
reabsorption and subsequent hypocalcemia and hypercalciuria

51. CALCIUM-LOADING TEST
In the traditional diagnostic approach, a calcium-loading test is performed, with the type of hypercalciuria
determined in the following ways:
 Absorptive hypercalciuria - During a defined period of fasting, patients with absorptive hypercalciuria
show a significant decrease in urinary calcium excretion;
 patients are then administered a large oral calcium meal, with urine samples obtained periodically
afterwards tending to show a great increase in the patient’s urinary calcium excretion
 Renal leak hypercalciuria –
 the kidney has an obligatory calcium-losing defect,
 patients are expected to show relatively little effect from dietary measures alone, including fasting;
following a large oral calcium meal, patients with renal leak hypercalciuria do not demonstrate as large
an increase in urinary calcium as do those with absorptive hypercalciuria

52. SIMPLIFIED APPROACH
The simplified approach is carried out as follows:
 Complete a medical history
 Carry out initial blood and 24-hour urine testing
 Identify hypercalciuric patients
 Check hypercalcemic patients for hyperparathyroidism with PTH levels; consider a thiazide challenge test if the PTH level alone is
inconclusive
 Check hypophosphatemic patients for hyperphosphaturia and possible absorptive hypercalciuria type III (renal phosphate leak
hypercalciuria); verify the diagnosis by determining the vitamin D-3 level or with a clinical trial of orthophosphate therapy
 Start a therapeutic trial of dietary modification treatment
 Repeat the blood and 24-hour urine tests
 If the hypercalciuria is controlled successfully with dietary modification, continue the therapy and repeat testing periodically; if dietary
modification is unsuccessful, consider a trial of thiazide therapy
 Orthophosphates are typically recommended if thiazides are not tolerated well or fail to control urinary calcium levels adequately; they
are particularly useful in hypercalciuric patients with elevated Vitamin-D levels; patients whose hypercalciuria fails all of these therapies
require further evaluation

53. Urinary calcium/osmolality ratio
 In children with decreased muscle mass, urinary calcium/osmolality ratio has been suggested as a
more specific and sensitive screening test than calcium/creatinine ratio because of decreased
urinary creatinine excretion in those patients. A urinary calcium/osmolality ratio (X 10) of less than
0.25 is considered to be suggestive of hypercalciuria.

54. Differentiation of absorptive from renal leak
hypercalciuria without a calcium-loading test
 Patients with renal leak hypercalciuria tend to have relatively low serum calcium levels in relation
to their serum parathyroid hormone (PTH) levels.
 Secondary hyperparathyroidism caused by an obligatory loss of serum calcium is a hallmark of
renal leak hypercalciuria. The calcium/creatinine ratio tends to be high (>0.20) in patients with
renal calcium leak, and these individuals are more likely than other hypercalciuric patients to have
medullary sponge kidney.
 A trial of dietary therapy with a restricted calcium diet is relatively ineffective with renal leak
hypercalciuria and is quite harmful in the long term because of possible bone decalcification,
negative calcium balance, and osteoporosis. Alkaline phosphatase and cyclic adenosine
monophosphate (cAMP) levels are often elevated in this condition.

55. Renal Leak Hypercalciuria Therapy
 Treatment of renal leak hypercalciuria is primarily with thiazides.
 Return calcium from the renal tubule to the serum,
 generally reduce urinary calcium levels by 30-40%, and
 eliminate secondary hyperparathyroidism.
 This hypocalciuric effect of thiazides is diminished or eliminated if dietary sodium is not restricted.
 Adverse effects of thiazides include
 an increase in uric acid and a decrease in urinary citrate;
 Hypokalemia.
 To correct these potential problems, potassium citrate often is administered to patients on long-term
thiazide therapy.

56.  Preferred forms of thiazide therapy include trichlormethiazide (Naqua) 2-4 mg/day and indapamide
(Lozol) 1.25-2.5 mg/day. These 2 medications can be administered just once a day and tend to carry
fewer adverse effects than do shorter-acting thiazides. Potassium citrate is often added to the
thiazide therapy to prevent hypokalemia and to increase urinary citrate levels. The dosage of
potassium citrate should be adjusted based on serum potassium and 24-hour urinary citrate levels.

57. Thank You