Renal lithiasis from a nephrologist’s perspective

Abstract

Man has known urinary lithiasis since antiquity. In Portuguese medicine, this is a pathology seen predominantly from the urology perspective, but renal lithiasis is evaluated and treated preventively by nephrologists worldwide, and its study has contributed significantly to knowledge of how the renal tubule works. Nephrolithiasis is a relatively common disease in the adult population and, in Portugal, is observed in about 7.3% of the population.
The main pathophysiological mechanisms of the most frequent types of kidney stones and who and how to conduct the metabolic research are briefly described. Medical treatment is also addressed, keeping in mind that nephrolithiasis is often accompanied by extra-renal manifesta- tions that should be investigated and treated, namely arterial hypertension, obesity, diabetes mellitus and osteo-metabolic disease.

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Renal lithiasis from a nephrologist’s perspective
Adelaide Serra, MD
Nephrology Department, Hospital Professor Doutor Fernando Fonseca, Amadora
PERSPECTIVE
Port J Nephrol Hypert 2019; 33(1): 3-6 • Advance Access publication 1 March 2019
 INTRODUCTION
Man has known urinary lithiasis since antiquity, with the first stones
identified in Egyptian mummies of about 8000 BC. The earliest written
references on urinary lithiasis and its forms of treatment are placed
between 3200 and 1200 BC, with lithotomy being described for the
first time between 600 BC and 600 BC1.
In Portuguese medicine, this is a pathology seen predominantly
from the urology perspective, but nephrolithiasis has always been
studied and treated from a medical point of view. Currently, renal
lithiasis is evaluated and treated preventively by nephrologists world-
wide, and its study has contributed significantly to knowledge of how
the renal tubule works. In the last decades, the contribution of urology
to the treatment of nephrolithiasis, with the development of kidney
stone destruction or removal techniques, has been extremely impor-
tant in solving obstructive complications, with the contribution of the
two specialties indispensable for the treatment and prevention of this
pathology.
Nephrolithiasis is a relatively common disease in the adult popula-
tion, with an overall prevalence in Western countries of 10% of the
adult population2. In Portugal, according to Domingos F et al3, its
prevalence is increasing, observed in about 7.3% of the population.
In recent decades, with industrialization and globalization, there
has been a progressive increase in the incidence of nephrolithiasis in
all Western countries. The causes for this increase seem to be related
to the improved standards of living seen after World War II4.
The disease is known mainly for its most common clinical mani-
festation – renal colic – although in many cases there may be no
symptoms, or minimal (calculi detected only at imaging or autopsy).
It usually has a benign course but, when untreated (or incorrectly
treated), recurrent nephrolithiasis is a chronic disease and may be
responsible for significant morbidity, loss of working days, high social
costs and loss of renal function. It is a cause of terminal chronic kidney
disease in 5% of European patients in renal replacement therapy5,6.
Despite all the available scientific evidence, if we exclude the treat-
ment of obstructive complications, no attempt is made to identify and
correct the risk factors of the disease in the overwhelming majority of
patients with nephrolithiasis. Preconceived ideas and lack of knowledge
of valid scientific principles have generalized the adoption of incorrect
recommendations and practices on the treatment of this disease.
 PATHOPHYSIOLOGY
Urine is a solution normally supersaturated in crystallization pro-
moters (calcium, urates, oxalate, phosphates). There are physico-
chemical conditions that can also favor the formation of stones, such
as urinary pH, the tubular flow rate of urine (urine output) or urinary
stasis.
The renal tubule has important defense mechanisms against the
formation of kidney stones (in its absence the formation of stones
would be universal!). The most important factor is the presence in
the urine of inhibitors of crystallization, aggregation, adhesion to the
tubular epithelium and growth of the calculi: citrate, magnesium,
pyrophosphate, Tamm-Horsfall protein (which, under certain physi-
cochemical conditions, can function as a promoter crystallization) and
other urinary macromolecules.
The formation of stones always represents an imbalance between
promoters and crystallization inhibitors (supersaturation of urine in a
certain salt) and / or alteration of the physicochemical conditions of
urine (low volume or urinary stasis, urinary pH). This change may be
occasional (dietary excesses, prolonged periods of water deprivation,
iatrogenic), or permanent as in patients with recurrent lithiasis.
 ABSTRACT
Man has known urinary lithiasis since antiquity. In Portuguese medicine, this is a pathology seen predominantly from the urology perspec-
tive, but renal lithiasis is evaluated and treated preventively by nephrologists worldwide, and its study has contributed significantly to knowledge
of how the renal tubule works. Nephrolithiasis is a relatively common disease in the adult population and, in Portugal, is observed in about
7.3% of the population.
The main pathophysiological mechanisms of the most frequent types of kidney stones and who and how to conduct the metabolic research
are briefly described. Medical treatment is also addressed, keeping in mind that nephrolithiasis is often accompanied by extra-renal manifesta-
tions that should be investigated and treated, namely arterial hypertension, obesity, diabetes mellitus and osteo-metabolic disease.
Received for publication: Dec 30, 2018 • Accepted in revised form: Jan 6, 2019 • http://doi.org/10.32932/pjnh.2019.04.002

4 Port J Nephrol Hypert 2019; 33(1): 3-6
Adelaide Serra
About 70-90% of the stones contain calcium, especially calcium
oxalate, with cystine, struvite, or pure uric acid (UA) being rare.
The formation of crystal nuclei is usually heterogeneous, with a
mixture of substances including uric acid. If nucleation occurs, conditions
for crystal growth and subsequent aggregation are met, with formation
of calculi that may be calcium oxalate, pure UA, struvite or other.
Regardless of the cause of renal lithiasis or the type of calculi,
adequate urine output (greater than 2 L / day) reduces urinary super-
saturation and contributes to the prevention of new stones.
Table 1 shows the urinary changes that may be present in each of
the major types of kidney stones.
Table 1
Urinary changes present in the various types of calculi
Type of calculi Urinary changes
Calcium oxalate Hyperoxaluria
Hypercalciuria
Hyperuricosuria
Hypomagnesuria
Hypocitraturia
Low urinary volume
Calcium phosphate Alkaline urine
Hypercalciuria
Hyperphosphaturia
Uric acid Persistently acidic urine
Low urinary volume
Hyperuricosuria
Struvite Infection with urease-producing bacteria
Cystine Poor cystine tubular reabsorption
Calcium oxalate
The majority of patients with calcium oxalate stones have hypercalciuria
(urinary excretion> 300 mg / day in men and> 250 mg / day in women,
or> 4 mg / kg in both) (Table 2). Hypercalciuria may be idiopathic (most
common, with a strong familial component) or may be due to renal tubular
acidosis, primary hyperparathyroidism, sarcoidosis, excess vitamin D or
glucocorticoids, hyperthyroidism or loop diuretics. It is also present when
there is an increased intake (and consequent excretion) of sodium; sodium
excretion correlates directly with calcium excretion, so it is not possible
to correct hypercalciuria without sodium excretion being normalized.
Hyperoxaluria may result from increased intestinal oxalate uptake
(increased ingestion or inflammatory conditions that facilitate the
absorption of oxalate), or increased endogenous production of oxalate
(a rare condition, responsible for primary hyperoxaluria). In the intes-
tine, calcium works as a chelator of oxalate; in situations of malabsorp-
tion, the free fatty acids in the intestine increase, calcium binds to
fatty acids and is no longer available to bind to the oxalate, which is
free in greater amounts to be absorbed. For this reason, there is no
advantage in systematically reducing calcium intake (except in situa-
tions of absorption hypercalciuria).
Hypocitraturia (<1.67 mmol / 24h or 320 mg / 24h) is present
mainly in inflammatory bowel diseases and renal tubular acidosis and
is an important cause of renal lithiasis, since citrate is an important
inhibitor of crystallization.
Hyperproteic and low carbohydrate diets produce a high acid load,
increasing the risk of stone formation (decreased urinary pH, decreased
calcium balance) and loss of bone mass.
Uric acid
The formation of UA calculi depends more on urinary pH than on
urinary excretion. Even if UA excretion and urinary volume are normal,
supersaturation in UA is always high when urinary pH is less than 5.5.
Calculi of UA are frequent in patients with metabolic syndrome
(diabetes mellitus, hypertension, obesity and hypertriglyceridemia),
probably due to a defect in ammonia production resulting from insulin
resistance7 and consequent reduction in urinary pH.
Cystine
Cystinuria is a relatively common, autosomal recessive genetic
disorder that results in a change in the gastrointestinal and renal
transport of cystine, ornithine, arginine, and lysine. Since cystine is
insoluble in acid urine, it will precipitate and form kidney stones.
Struvite
Struvite calculi arise in situations of chronic upper urinary tract
infections by urease producing bacteria: Proteus spp, Haemophilus
spp, Klebsiella spp and Ureaplasma urealyticum. Urease promotes
Table 2
Measured urinary parameters
Parameter Reference values
Calcium Female: <6.25 mmol / 24h (250 mg / 24h)
Male: <7.5 mmol / 24h (300 mg / 24 h)
Oxalate < 0.5 mmol/24h (45 mg/24h)
Uric acid < 3.54 mmol/24h (600 mg/24h)
Citrate > 1.67 mmol/24h (320 mg/24h)
pH –
Volume > 2 L /24h
Sodium < 200 mEq/24 h
Potassium 25 – 125 mEq/24h
Phosphorus 16 – 35,5 mmol/24h (0.5 – 1.1 g/24h)
Magnesium 2.47 – 4.94 mmol/24h (60 – 120 mg/24h)
Sulphate < 25 mmol/24h
Urea Variable
Creatinine Variable
Ammonia < 40 mEq/24h
Cystine Negative in qualitative test
<280 μmol / g creatinine

Port J Nephrol Hypert 2019; 33(1): 3-6 5
the hydrolysis of urea, with the production of ammonia and, con-
sequently, the creation of persistently alkaline urine that favors
the formation of magnesium ammonium phosphate (struvite)
stones. They are most often coraliform stones and occur mainly in
women and in individuals with chronic obstructions of the urinary
tract.
 METABOLIC EVALUATION
The metabolic study of renal lithiasis is expensive and cumbersome,
and is not indicated in all patients. Individuals with documented recur-
rent (> 2) episodes of renal colic, or individuals with only one episode
of renal colic (or even with asymptomatic renal lithiasis) but with
family history of renal lithiasis, single kidney, inflammatory bowel
disease, osteo-metabolic disease, recurrent urinary tract infections,
uric gout, medullar sponge kidney or nephrocalcinosis, should be
referred to the Nephrology-Renal Lithiasis clinic to perform a complete
evaluation (Figure 1).
In the anamnesis, the number and periodicity of the episodes
should be investigated, if there were previous treatments (and which)
and possible complications, if there are concomitant pathologies or
a family history of renal lithiasis. A small questionnaire on dietary
habits, such as fluid intake, calcium intake, oxalates, salt and animal
proteins, should be carried out. In usual medication, drugs such as
calcium channel blockers, ascorbic acid, furosemide, calcium and / or
vitamin D, antacids, uricosuric agents, triamterene or acetazolamide
and theophylline should be investigated.
For individuals who are indicated for a more complete evaluation,
blood and 24-hour urine collections should be performed. This study
should not be performed less than 6 weeks after an episode of renal
colic or urologic intervention on the urinary tract.
Biochemical analyses to identify patients with secondary causes
of renal lithiasis include creatinine, calcium, phosphorus, uric acid,
alkaline phosphatase, iPTH, sodium, potassium and chlorine. In
24-hour urine, calcium, oxalate, citrate, uric acid, magnesium, sodium,
potassium, chlorine and cystine should be analysed. Urinary phos-
phate, urea and sulfate should be measured as indirect markers of
protein consumption. Urinary volume should be quantified and urinary
pH measured prior to the addition of any preservative into the urine.
Urine creatinine is measured to evaluate the correction of urine col-
lection, and a urine culture must be taken to exclude the presence of
urinary tract infection. Whenever possible, fresh urine should be col-
lected for crystaluria. When it is possible to obtain, renal calculi should
be analysed, preferably by infrared spectrophotometry.
The imaging evaluation should always include a renal ultrasound,
and a simple abdominal X ray if the identified calculi are greater than
5 mm. If there is clinical suspicion of medullar sponge kidney, presence
of urinary malformations, obstruction or unilateral renal dysfunction,
renal CT with contrast may be performed.
 MEDICAL TREATMENT
Whatever the type of calculi, the first step in treating renal lithiasis
is always a fluid intake that allows a diuresis of more than 2 liters.
Some dietary and pharmacological measures are suggested to
control the most frequent types of kidney stones.
Calcium oxalate
• Hypercalciuria
– Diet: restriction of sodium intake and adequate intake of cal-
cium (between 400-800 mg / day)
– Drugs: Thiazides (increases calcium reabsorption)
• Hyperoxaluria
– Diet: restriction of intake of oxalates (nuts, dark green vege-
tables, beets, citrus fruits, etc.)
– Drugs: do not supplement with vitamin C; in patients with enteral
hyperoxaluria there may be a need for calcium supplements,
which should be given during meals as oxalate chelators
• Hyperuricosuria
– Diet: restriction of animal protein
– Drugs: allopurinol
• Hypocitraturia
– Diet: increased consumption of vegetable fiber and fruit
– Drugs: potassium citrate
Uric acid
• Diet: restriction of the consumption of proteins (mainly animal)
• Drugs: potassium citrate for alkalinisation of urine; Allopurinol
if serum uric acid> 8 mg / dL and / or urinary> 800 mg / 24h
Cystine
• Diet: ingestion of liquids to obtain a diuresis of more than 3
liters
Renal lithiasis from a nephrologist’s perspective
Figure 1
Metabolic evaluation

6 Port J Nephrol Hypert 2019; 33(1): 3-6
Adelaide Serra
• Drugs: potassium citrate for alkalinisation of urine; captopril,
penicillamine if urinary cystine> 300 μmol / g creatinine (bind
to cystine and form soluble complexes)
Struvite
• Diet: ingestion of liquids to obtain a diuresis of more than 2
liters
• Drugs: prolonged antibiotic therapy
• Removal of existing calculi
• Consider urine acidification (cranberry)
 MORBIDITY
I cannot conclude without mentioning that in addition to renal
complications related to repeated episodes of renal colic and urologic
procedures and eventual loss of renal function, nephrolithiasis is often
accompanied by extra-renal manifestations that should be investigated
and treated, namely arterial hypertension, obesity, diabetes mellitus
and osteo-metabolic disease.
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Correspondence to:
M Adelaide Serra, MD
Nephrology Department, Hospital Professor Doutor Fernando Fonseca, Amadora
E-mail: maria.a.serra@hff.min-saude.pt