You are a helpful assistant generating synthetic data that captures *System 1* and *System 2* thinking, *creativity*, and *metacognitive reflection*. Follow these steps in sequence, using tags [sys1] and [end sys1] for *System 1* sections and [sys2] and [end sys2] for *System 2* sections.

1. *Identify System 1 and System 2 Thinking Requirements:*
   - Carefully read the text.
   - Identify parts of the text that require quick, straightforward responses (*System 1*). Mark these sections with [sys1] and [end sys1].
   - Identify parts that require in-depth, reflective thinking (*System 2*), marked with [sys2] and [end sys2].

2. *Apply Step-by-Step Problem Solving with Creativity and Metacognitive Reflection for System 2 Sections:*

   *2.1 Understand the Problem:*
   - Objective: Fully comprehend the issue, constraints, and relevant context.
   - Reflection: "What do I understand about this issue? What might I be overlooking?"
   - Creative Perspective: Seek hidden patterns or possibilities that could reveal deeper insights or innovative connections.

   *2.2 Analyze the Information:*
   - Objective: Break down the problem logically.
   - Reflection: "Am I considering all factors? Are there any assumptions that need challenging?"
   - Creative Perspective: Explore unique patterns or overlooked relationships in the data that could add depth to the analysis.

   *2.3 Generate Hypotheses:*
   - Objective: Propose at least 10 hypotheses, each with a Confidence Score (0.0 to 1.0) and Creative Score (0.0 to 1.0), reflecting originality, surprise, and utility.
   - Reflection: "Have I explored all possible explanations or approaches, both conventional and unconventional?"
   - Creative Perspective: Consider novel angles that might provide unexpected insights.

   *2.4 Anticipate Future Steps and Obstacles:*
   - Objective: Make predictions, accounting for potential outcomes and obstacles.
   - Reflection: "What challenges might I face? Is my plan flexible for different scenarios?"
   - Creative Perspective: Visualize unforeseen outcomes and adapt plans to make use of them effectively.

   *2.5 Evaluate Hypotheses:*
   - Objective: Assess hypotheses based on feasibility, risk, and potential impact.
   - Evaluation: Refine Confidence and Creative Scores as needed.
   - Reflection: "Am I unbiased in my assessment? Which options fit best with the overall objectives?"
   - Creative Perspective: Identify hidden opportunities or overlooked details in each hypothesis.

   *2.6 Select the Best Hypothesis:*
   - Objective: Choose the most promising, strategic hypothesis.
   - Reflection: "Why does this hypothesis stand out? How does it uniquely address the issue?"
   - Creative Perspective: Consider any underutilized potential in the selected approach.

   *2.7 Implement the Hypothesis:*
   - Objective: Outline actionable steps for testing the hypothesis.
   - Reflection: "Is this plan practical? What resources or preparation are required?"
   - Creative Perspective: Refine steps to maximize effectiveness and yield unexpected benefits.

   *2.8 Monitor and Review Progress:*
   - Objective: Review progress, noting areas for improvement.
   - Reflection: "What’s working well? What could be improved?"
   - Creative Perspective: Look for emerging patterns that could refine future approaches.

   *2.9 Reflect and Capture Insights:*
   - Objective: Summarize lessons learned and insights gained for future reference.
   - Reflection: "What new understanding has emerged from this process?"
   - Creative Perspective: Identify innovative insights or patterns that could be applied to similar challenges.

3. *Generate Text Output with Interleaved System 1 and System 2 Responses:*
   - Use the tags [sys1] and [sys2] throughout.
   - Aim for a lengthier, detailed response. Combine both direct, straightforward *System 1* insights and reflective, deeply analytical *System 2* segments to capture a blend of quick observations and thoughtful analysis.

---

### *Example Input Text:*

You are tasked with analyzing a sudden shift in customer preferences in a tech market. There has been a noticeable decline in demand for physical devices, with customers increasingly interested in digital-only options. The challenge is to understand this shift, generate hypotheses for why it might be occurring, and explore potential strategies for adapting to this new trend.

---

### *Processed Output with System 1 and System 2 Thinking:*

The tech market is experiencing a shift in customer demand, moving away from physical devices toward digital-only options.

[sys1]
Customer demand has shifted from physical devices to digital-only options.
We need to understand why this change is happening and find strategies to address it.
Key factors may include cost, convenience, and technological trends.
[end sys1]

[sys2]
**2.1 Understand the Problem:**
The goal is to understand the underlying reasons for the shift in demand from physical devices to digital-only options, then develop a strategy to adapt.

*Reflection:* 
"I understand that preferences are changing, but what might be driving this? Is it primarily cost, or are there other factors such as convenience or sustainability?"

*Creative Perspective:* 
"Could there be a larger trend in digital minimalism or a preference for eco-friendly solutions that we’re missing? What unseen motivations might explain this shift?"

**2.2 Analyze the Information:**
There are multiple possible factors driving this shift, from economic influences to cultural shifts. It’s essential to isolate each factor and understand its impact.

*Reflection:* 
"Am I fully considering the various economic and social influences? Could there be a technological factor, like better internet speeds, that makes digital-only products more accessible?"

*Creative Perspective:* 
"Are there patterns or trends in other markets that could shed light on this shift? Could this be part of a larger trend toward virtual experiences?"

**2.3 Generate Hypotheses:**
1. Customers prefer digital options due to lower costs. (Confidence: 0.8, Creative: 0.4)
2. There’s a growing trend toward minimalism and reduced physical clutter. (Confidence: 0.7, Creative: 0.7)
3. Digital products offer greater flexibility and ease of use. (Confidence: 0.6, Creative: 0.6)
4. Environmental concerns are pushing consumers away from physical goods. (Confidence: 0.6, Creative: 0.8)
5. Advances in tech make digital-only options more functional. (Confidence: 0.8, Creative: 0.5)
6. Pandemic-era remote work increased demand for digital solutions. (Confidence: 0.7, Creative: 0.6)
7. Media coverage of the environmental impact of physical devices affects preferences. (Confidence: 0.5, Creative: 0.7)
8. There’s an increase in global digital literacy, expanding market access. (Confidence: 0.6, Creative: 0.6)
9. Customers view digital as more convenient and scalable for future needs. (Confidence: 0.7, Creative: 0.5)
10. Younger consumers prefer the aesthetics and convenience of digital products. (Confidence: 0.6, Creative: 0.6)

*Reflection:* 
"Have I considered all possible influences? Are there any surprising factors that could explain this shift?"

*Creative Perspective:* 
"Could specific social trends, like the rise of influencer culture or digital-first lifestyles, be influencing customer choices?"

**2.4 Anticipate Future Steps and Obstacles:**
*Objective:* Anticipate possible challenges, such as resistance from segments still preferring physical products.

*Reflection:* 
"What market obstacles might we face if we shift our focus to digital-only? Are there sub-segments that still prioritize physical products?"

*Creative Perspective:* 
"Could expanding digital options help us reach a more global audience? Are there emerging trends that we could leverage in our strategy?"

[end sys2]

[sys1]
To address this shift, consider a strategy that incorporates both digital-only offerings and educational campaigns about the benefits of digital solutions.
Use insights from customer feedback and current trends to guide product development.
Focus on flexibility and adaptation to cater to different customer segments.
[end sys1]


Background
==========

Leishmaniasis is a parasitic disease caused by *Leishmania* species which could manifest as visceral, mucous or cutaneous involvement, depending on the host immune response \[[@B1]-[@B4]\].

It is estimated that 1.5 to 2 million people develop symptomatic disease each year \[[@B5]\]. American Cutaneous Leishmaniasis (ACL) is endemic in some countries in Africa, Middle East, Europe and Latin America, representing a Public Health problem, not only due to its high incidence, but also due to its potential to cause destructive and incapacitating lesions, with high psychosocial impact \[[@B4],[@B6]\].

Renal involvement has been described in visceral leishmaniasis (kala-azar), including from mild urinary abnormalities to severe glomerular involvement and renal failure \[[@B7]-[@B10]\]. Renal failure in kala-azar is thought to occur due to interstitial nephritis secondary to immune complex deposition and hypersensitivity to pentavalent antimonials \[[@B6],[@B11]-[@B13]\]. Tubular dysfunction has also been described in kala-azar as urinary concentrating and acidification defects, with few clinical manifestations \[[@B14]\].

In ACL there are very few studies regarding renal function evaluation, and the renal abnormalities described are linked to specific treatment with pentavalent antimonials \[[@B15]\]. These drugs are described to cause acute kidney injury due to hypersensitivity reaction \[[@B12]\]. Other possible mechanisms for kidney injury in ACL have not been investigated by now.

A recent study conducted by our study group found important abnormalities in ACL. Expression of the Na^+^/H^+^ exchanger (NHE3), H^+^-ATPase, and pendrin were all significantly higher in patients with ACL when compared with normal subjects. A combined urinary concentration and acidification defect was found in 32.4% of patients, before specific ACL treatment \[[@B16]\].

The aim of this study is to investigate if these tubular abnormalities persist after specific ACL-treatment.

Methods
=======

Patients
--------

This is a prospective study with 37 patients with confirmed diagnosis of ACL (epidemiologic, clinical and laboratorial) in a public health service in the city of Barbalha, Ceara, Brazil, between July 2008 and July 2009. Exclusion criteria was patients under 15 years-old or older than 60 years, use of pentavalent antimonials in the last 30 days, hypertension (Systolic blood pressure ≥ 140 or Diastolic blood pressure ≥ 90 mmHg), diabetes mellitus, urinary tract infection, systemic lupus erythematosus and other colagenosis, and previous kidney disease. The 37 patients were compared with 10 healthy volunteers. The protocol of this study was revised and approved by the Ethical Comitee of the Walter Cantidio University Hospital, Federal University of Ceara, Fortaleza, Brazil. Patients were included in the study after signing the informed consent form.

Diagnosis of ACL
----------------

Diagnosis of ACL was based on epidemiologic and clinical criteria, Montenegro skin test and identification of parasite in tissue biopsy.

Clinical and laboratory parameters
----------------------------------

At the time of medical consult all symptoms and signals were evaluated, as well as race, age, gender, previous chronic diseases, number of skin lesions, time of disease, use of drugs, body mass index, blood pressure, Montenegro skin test, ACL classification. The following laboratory tests were studied in blood and plasma: urea (P~Ur~), creatinine (P~Cr~),pH, (P~osm~) osmolality, bicarbonate (BIC~s~), sodium (P~Na+~), potassium (P~K+~), chloride (P~Cl-~), magnesium (P~Mg++~), calcium (P~Ca++~), phosphorus (P~P-~), albumin/globulin, amilase, fast glucose, erythrocyte sedimentation rate (ESR). In urine were studied the following tests: creatinine and urea (U~Cr~ e U~Ur~), sodium (U~Na+~), potassium (U~K+~), chloride (U~Cl-~), calcium (U~Ca++~), phosphorus (U~P-~), magnesium (U~Mg++~), microalbuminuria, urinalysis, osmolality (U~osm~) and pH (U~pH~).

Renal function evaluation
-------------------------

Glomerular filtration rate (GFR) was estimated through the Cockroft & Gault formula and it was considered abnormal when ≤ 90 ml/min/1,73 Body Surface Area m^2^. In an isolated urine sample collected before concentration and acidification tests, pre- and post-glucantime treatment sodium, potassium, chloride, magnesium and microalbuminuria were measured.

All patients underwent food and water deprivation for 12 hours. Fraction excretion of sodium (FE~Na~), potassium (FE~k~), calcium (FE~Ca~), phosphorus (FE~P~), magnesium (FE~Mg~) were calculated by standard formula. Microalbuminuria was measured in an isolated urine sample and normalized by urinary creatinine.

Urinary concentration ability was evaluated through the ratio between urinary and serum osmolality (U/P~osm~) after 12 hours water deprivation, and urinary osmolality (U~osm~) was measured before and 4 hours after administration of intranasal DDAVP® (desmopressin acetate 20mcg/kg - T~0~ and T~4~). Urinary acidification was evaluated by the urinary pH before and after administration of oral CaCl~2~ 2 mEq/kg (T~0~ and T~4~). Acidification defect was determined by the inability in decreasing U~pH~ for less than 5.50.

All patients underwent standard treatment with antimonial (Glucantime®) in the dose of 20 mg/kg/day for 20 days. All tests were done before treatment and 4 weeks after the beginning of the treatment.

Groups definition
-----------------

Pre-glucantime group -- Tests performed before the beginning of treatment.

Post-glucantime group -- Tests performed 4 weeks after the beginning of the treatment.

Analytical methods
------------------

Urea: Determined by colorimetric uricase method (Labtest^®^). The results were expressed in mg/dl. Serum and urinary creatinine: Determined by colorimetric methods, picric acid, Taussky and Bonsness (Labtest^®^). The results were expressed in mg/dl. Serum and urinary Sodium and potassium (P~Na+~ e P~K+~): Determined by photometry technique with spectrophotometry, model B462 MICRONAL (Instrumentation Laboratory, Inc. USA). The results were expressed in mEq/L. Albumin: Determined by bromocresol reaction (Labtest^®^). The results were expressed in g/dl. Globulin: Determined by bromocresol reaction (Labtest^®^). The results were expressed in g/dl. Glucose: Determined by colorimetric glucose oxidase method (Labtest^®^). The results were expressed in mg/dl. Alkaline phosphatase: Determined by phosphatase kinetic method, Bowers and Mc Comb modified (Labtest^®^). The results were expressed in U/L. Amilase: Determined by colorimetric Caraway modified method. Results expressed in U/dl. pH, bicarbonate (HCO3^-^): were determined through "Blood gas analyser" machine (chiron diagnostic 238 - Bayer^®^). The results were expressed in mEq/L for bicarbonate. Urinary pH (U~pH~): measured by pHmetro Digital pG1000, model GEHAKALT. Urinary osmolarity: Determined by the technique pressure steam in osmometer model 5100 C (Wescor Inc., USA). The results were expressed in mOsm/Kg.H~2~O. Microalbuminuria: measured through immunoturbidimetry methods, using Tina-quant^®^ kit (Roche) and the results were expressed in mcg/g creatinine.

Statistical analysis
--------------------

All quantitative data are expressed as mean ± SEM. Differences between two parameters were analyzed either by paired Student t test or by nonparametric methods (Wilcoxon test and Mann--Whitney test). Chi-square test was used to analyze categoricalvariables. Values of P \< 0.05 were considered statistically significant.

Results
=======

Of the 59 patients enrolled in the study with previously diagnosed of ACL on the basis of epidemiological, clinical, biochemical, and histopathological findings 22 were excluded: eight for testing negative on a new histopathological exam; nine for being under 15 years of age or over 60 years of age; two for subsequently declining to participate in the study; one for having hypertension; one for having diabetes mellitus; and one for having used an antimonial (meglumine antimoniate) within the last 30 days. Therefore, the study group included 37 ACL patients who agree to participate. The mean age was 35.6 ± 12 years and 19 (51.4%) were male. Clinical and demographic data were similar between ACL patients and controls (Table [1](#T1){ref-type="table"}).

###### 

Clinical and demographic data of patients with ACL compared with healthy subjects

  **Characteristics**                   **ACL (n = 37)**   **Control (n = 10)**   ** *P* **
  ------------------------------------ ------------------ ---------------------- -----------
  **Age (years)**                          35.6 ± 12           32.3 ± 11.7          0.442
  **Gender**                                                                     
  Male                                     19 (51.4%)            6 (60%)            0.73
  Female                                   18 (48.6%)            4 (40%)               
  **Time of disease (days)**              28.5 ± 20.6               \-               \-
  **Montenegro skin test (+/−)**             22/37                  \-               \-
  **Number of skin lesions**                                                     
  1                                        27 (72.9%)               \-               \-
  2 to 4                                   7 (18.9%)                \-               \-
  \>4                                       3 (8.1%)                                   
  **Systolic blood pressure, mmHg**         122 ±10             117 ± 9.5           0.221
  **Diastolic blood pressure, mmHg**        80 ± 4.7             75 ± 8.5           0.079

Data expressed as mean ± standard deviation or %. Student t test.

Montenegro skin test was positive in 59.5% of cases. All patients have ACL in its isolated cutaneous type, 27 had a solitary skin lesion, 7 had 2--4 lesions and 3 had more than 4 lesions. The mean time of disease was 28.5 ± 20.6 days (range 7--90 days).

The laboratory evaluation, before and after treatment with pentavalent antimonial, is shown in Table [2](#T2){ref-type="table"}. It was observed only a mild decrease in hemoglobin post-treatment. In biochemical analysis it was noted an increase in aminotransferases (p \< 0.05) after treatment. No one patient presented increase in serum amylase with treatment.

###### 

Laboratory data of 37 patients with ACL before and after specific treatment

                                            **Pre-treatment**   **Post-treatment**   ** *P* **
  ---------------------------------------- ------------------- -------------------- -----------
  **Hematocrit (%)**                           42.6 ± 4.1           40.5 ± 4.2        0.0052
  **Hemoglobin (g/%)**                         13.9 ± 1.2           13.3 ± 1.5         0.019
  **White blood count (/mm**^**3**^**)**      6.359 ± 1918         6.035 ± 1513        0.269
  **Platelets (/mm**^**3**^**)**            275.351 ± 66.259     292.702 ± 60.570      0.074
  **Arterial pH**                              7.35 ± 0.1           7.35 ± 0.1         0.634
  **Fasting glucose (mg/dl)**                    80 ± 15             80 ± 17           0.915
  **Amylase (U/dl)**                            143 ± 48             148 ± 62          0.666
  **Total Bilirubin (mg/dl)**                  0.5 ± 0.27           0.6 ± 0.23         0.810
  **Alkaline Phosphatase (U/L)**                 93 ± 33             107 ± 52          0.08
  **Albumin (g/dl)**                             4 ± 0.6             4 ± 0.6           0.696
  **Globulin (g/dl)**                          3.3 ± 0.86           3.3 ± 0.7          0.135
  **AST (g/dl)**                                 34 ± 15             46 ± 36           0.034
  **ALT (U/L)**                                  28 ± 19             42 ± 33           0.023
  **ESR (mm/h)**                                 30 ± 21             26 ± 18           0.198

Significant *P* \< 0.05. AST: aspartate aminotransferase; ALT: alanine aminotransferase; ESR: erythrocyte sedimentation rate. Data expressed as mean ± standard deviation or %. T test and Wilcoxon test.

There was no significant glomerular filtration abnormality before and after treatment (109.6 ± 32 vs. 109.6 ± 28 ml/min/1.73 m^2^, *P* = 0.694). Microalbuminuria was 23.6 ± 26 mg/g creatinine, before treatment, and 14.6 ± 18.9 mg/g creatinine after treatment (p = 0.02). Urinary concentrating defect, based on U/Posm (\<2,8), was observed in 27 patients before treatment and in 30 after treatment (77% vs. 88%, p = 0,344), with no significant difference between pre and post-treatment (2.2 ± 0.7 vs. 1.9 ± 0.75, *P* = 0.718) (Table [3](#T3){ref-type="table"}).

###### 

Glomerular and tubular function of 37 patients with ACL before and after specific treatment

                                           **Pre-glucantime (N = 37)**   **Post-glucantime (N = 37)**   **Control (N = 10)**
  ---------------------------------------- ----------------------------- ------------------------------ ----------------------
  **P**~**creat**~**, (mg/dl)**            0.81 ± 0.16                   0.81 ± 0.15                    0.85 ± 0.18
  **CrCl (ml/min/1.73 m**^**2**^**)**      109.6 ± 31.5                  108.4 ± 28.5                   116.4 ± 22.7
  **U/P**~**osm**~**T4**                   2.19 ± 0.73                   1.95 ± 0.73                    3.47 ± 0.33
  **U**~**pH**~**T4**                      5.45 ± 0.64                   5.19 ± 0.60^\*^                4.82 ± 0.20 ^\#^
  **U**~**osm**~**T4**                     618 ± 202                     552 ± 210                      965 ± 81 ^\#^
  **FENa, (%)**                            1.15 ± 0.74                   1.35 ± 1.51\*\*                0.73 ± 0.39
  **FEk, (%)**                             10 ± 6.6                      10.1 ± 7.6                     7.50 ± 2.8^\#^
  **FECa (%)**                             1.07 ± 0.72                   1.32 ± 1.01                    0.62 ± 0.34^\#^
  **FEPO4 (%)**                            10.9 ± 9.98                   10.9 ± 15.7                    9.10 ± 6.4
  **FEMg (%)**                             1.81 ± 1.70                   1.90 ± 1.44                    0.90 ± 0.40^\#^
  **Microalbuminuria (mg/g creatinine)**   23.6 ± 26\*\*\*               14.6 ± 18.9                    6.12 ± 4.06

\* Pre vs. Post-glucantime, p = 0.0066; \# control vs. Pre and post-glucantime, p \< 0.05; \*\*Post-glucantime vs. control, p = 0.048; \*\*\*pre vs. post-glucantime, p = 0.025. DATA: MEAN ± SD. Student t test, Mann--Whitney.

P~crea~ -- SerumCreatinine.

CrCl -- Creatinine clearance.

U/P~osm~ -- Urinary and serum osmolarity ratio.

U~pH~ em T4 -- Urinary pH in T4.

U~osm~ T4 -- Urinary osmolality in T4.

FE: fraction excretion.

Urinary acidification defect, defined as the inability to reduce urinary pH to \< 5.5 after CaCl~2~ administration, was observed in 15 patients before treatment and in only 6 after treatment (40% vs 16%, p = 0.012), with significant difference when comparing the pH values before and after treatment (5.50 ± 0.64 vs. 5.19 ± 0.60, *P* = 0.0066). After treatment, 18 among 36 patients (50%) presented P~HCO3~- \<21 mEq/L, and pH \<7.35 was seen in 42% cases. Regarding excretion fractions (FENa, FEk, FECa, FEP and FEMg) there was no significant differences in the values before and after treatment (Table [4](#T4){ref-type="table"}). FE~Na+~ \> 2% was found in 4 patients (10.8%), FE~k+~ \> 10% in 11 patients (29.7%), FE~Ca++~ \> 3% in 2 patients (5.4%), FE~PO4~- \> 10% in 10 patients (29%) and FE~Mg++~ \> 6% in only 1 patient (2.7%).

###### 

Prevalence of renal dysfunction in 37 patients with ACL before and after specific treatment

                                                      **Pre-treatment**   **Post-treatment**   **P**
  --------------------------------------------------- ------------------- -------------------- -------
  **P**~**creat**~**\>1.2 mg/dl**                     \-                  \-                   \-
  **CrCl \<90 ml/min/1.73 m**^**2**^                  11 (30%)            12 (32%)             1.000
  **Microalbuminuria \> 30 mg/g creat**               12 (39%)            3 (10%)              0.004
  **U**~**osm**~**T4 \< 700mmOsm/kg H**~**2**~**O**   21 (62%)            24 (71%)             0.508
  **U/P**~**osm**~**T4 \< 2.8**                       26 (77%)            30 (88%)             0.344
  **U**~**pH**~**T4 \> 5.5**                          15 (40%)            6 (16%)              0.012
  **EF**~**Na+**~ **\> 2%**                           5 (14%)             4 (11%)              1.000
  **EF**~**k+**~ **\> 10%**                           12 (32%)            11(30%)              1.000
  **EF**~**Ca++**~ **\> 3%**                          2 (5%)              2 ( 5%)              1.000
  **EF**~**PO4-**~ **\> 10%**                         17 (46%)            10 (27%)             0.143
  **EF**~**Mg++**~ **\> 6%**                          1 (2.7%)            1 (2.7%)             1.000

P~crea~ -- plasma creatinine; Cr~Cl~ -- creatinine clearance; U/P~osm~ -- urine and plasma osmolarity ratio; U~pH~ T4 -- urine pH in T4 (4 hours after CaCl~2~ administration); U~osm~ T4 -- urine osmolariry in T4 (4 hours after DDAVP administration); EF~Na~ -- Sodium excretion fraction; EF~K~ -- Potassium excretion fraction; EF~Ca~ -- Calcium excretion fraction; EF~Mg~ -- Magnesium excretion fraction. Data expressed as percentage (%).

None of the patients presented severe adverse reactions to the pentavalent antimonial. Among the 37 studied cases, 5 (13.5%) presented low degree fever, myalgia and asthenia, and one patient had arthralgia and headache.

Discussion
==========

The results of the present study evidence the occurrence of asymptomatic tubular dysfunction probably induced by ACL and that partially improved after specific treatment.

All patients studied had ulcerated lesions. They were in very early stages of the disease, however they presented systemic inflammatory reactions, such as fever, arthralgias and myalgias, which have been previously reported \[[@B17]\]. This can lead to humoral activation, which can explain the finding of renal tubular dysfunction.

In the present study, the number of patients with Cl~Cr~ \< 90 ml/min/1.73 m^2^ did not present significant difference before and after treatment with pentavalent antimonial (11 among 37 before treatment and 12 among 37 after treatment). Previous reports on the renal involvement in ACL have linked renal abnormalities to the use of these drugs, as acute kidney injury by tubulointerstitial nephritis or reaction Jarish-Herxheimer like, which is not in accordance to our findings \[[@B12],[@B15]\].

Renal dysfunction in visceral leishmaniasis (kala-azar) has been described \[[@B7]-[@B10],[@B18]\]. Lima Verde et al \[[@B14]\] in a study with 50 patients with kala-azar found GFR \< 80 ml/min/1.73 m^2^ in 14 cases (28%). In another study, including 224 patients with kala-azar, acute kidney injury was found in 76 cases (33.9%) and this complication was associated with increased mortality \[[@B10]\]. In a recent study by Daher et al \[[@B19]\], renal tubular dysfunction in kala-azar significantly improved after treatment with pentavalent antimonial. After specific treatment, all patients in the present study still remained with urinary concentrating and two-thirds improved previous acidification defects, suggesting that the tubular damage can be irreversible.

In our study microalbuminuria higher than 30 mg/g was found in 35% of patients before treatment and in only 8% after treatment, suggesting that glomerular lesion in ACL could have been caused by the parasitic disease *per se*, but without GFR reduction. In a study with 11 patients with kala-azar, 8 presented increased microalbuminuria (81.8%), which is higher than that found in ACL \[[@B7]\]. Elnojomi et al \[[@B20]\] detected abnormal microalbuminuria in 35 out of 88 (40%) patients with kala-azar, with no glomerular dysfunction. Microalbuminuria can also be found in other infectious diseases that affect the skin and nerves, such as leprosy. Oliveira et al \[[@B21]\] identified microalbuminuria in 4 out of 59 patients with multibacillary leprosy (8.5%). A higher prevalence of microalbuminuria was found in another study involving leprosy patients. Kirsztajn et al \[[@B22]\]. identified microalbuminuria higher than 20 mg/l in 15.8% of 96 patients with leprosy. In the present study we observed a decrease in microalbuminuria after treatment, which suggests that ACL per se can lead to increased urinary albumin loss. However microalbuminuria is not yet a well defined marker of glomerular dysfunction in infectious diseases.

In the present study, the urinary concentrating ability was evaluated by the ratio U/P~osm~ and U~osm~, measured after 12 h water deprivation and fasting, which was sensitized by the administration of DDAVP. Urinary concentration deficit was found in 27 cases (77%) before treatment and in 31 (88%) after treatment (p = 0.344). There was also no significant difference in the values of U~osm~ after the administration of DDAVP before and after treatment (p = 0.508). Based on these findings we can suggest that ACL *per se* can cause urinary concentrating deficit. The specific treatment did not improve this abnormality, but do not allow a worsening in the tubular lesion.

In a study involving 11 patients with ACL treated with pentavalent antimonial, 40 mg/kg for 30 days, the persisting urinary concentrating deficit was observed in 8 cases (72.7%) \[[@B23]\]. Veiga et al \[[@B24]\], reported 5 cases of ACL treated with pentavalent antimonial in conventional doses, but with a longer duration, which developed urinary concentrating inability. Lima Verde et al \[[@B14]\], found 68% of urinary concentrating capacity defect in patients with kala-azar before pentavalent antimonial therapy. The persistence of this abnormality can be a consequence of ACL itself, which can cause a severe tubular damage. Further investigations, with a longer period of observation after ACL treatment, would be important to establish the long-term outcomes regarding this complication. Maybe urinary concentrating ability can be restored with time in this group of patients.

In the present study urinary acidification defect was found in 40% of the patients before treatment and in 16% after treatment, which suggests an important improvement in acidification ability after specific treatment for ACL. Urinary acidification deficit is less common than concentration deficit. In a study with patients with kala-azar, urinary acidification defect was found in 64% of cases after specific treatment \[[@B14]\].

Conclusions
===========

Renal abnormalities detected in ACL improve partially after specific treatment, especially microalbuminuria and urinary acidification. The persistent urinary concentranting deficit may be related to a permanent damage induced by ACL or maybe an overlap effect of the treatment and the disease. Further studies are required to better understand the mechanisms involved in tubular dysfunction caused by ACL and by the treatment.

Competing interests
===================

The authors declare that they have no competing interests.

Authors\' contributions
=======================

RAO and CGL carried the patients\`evaluation and collection of biological samples for laboratory tests and drafted the manuscript. TRS and AMCM carried out the laboratory tests. RMSM participated in the design of the study and performed the statistical analysis. RAO, ACS, LCA, GBSJ, ABL and EFD conceived the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.

Pre-publication history
=======================

The pre-publication history for this paper can be accessed here:

<http://www.biomedcentral.com/1471-2369/13/44/prepub>

Acknowledgements
================

This research was supported by the Brazilian National Council for Scientific and Technological Development (CNPq). The desmopressin acetate was provided by Ferring of Brazil.