Contrast media-induced nephropathy in Tunisia: prospective case-control study with cardio-nephrological monitoring.

Introduction: vascular opacification using iodinated contrast media (ICM) is often the primary diagnostic and therapeutic approach. However, the risk of post-injection nephrotoxicity of ICM is significantly higher in patients with underlying nephropathy. This study aimed to determine the incidence of Contrast Media Induced Nephropathy (CMIN) and identify predictive factors for its occurrence in patients from a cardiology department. Methods: our prospective study involved 158 patients who underwent coronary angiography or angioplasty at the cardiology department between December 2017 and May 2018. Two types of ICM were used in our study: Iopromide and Iohexol. All patients received either physiological serum (9‰) or bicarbonate serum (14‰) intravenously for hydration. We defined impaired renal function as an increase in creatinine ranging from 10 to 26 µmol/L, while CMIN was defined as an increase in serum creatinine exceeding 26.5 µmol/L. We investigated the factors associated with CMIN using logistic regression analysis. Results: the mean age of our patients was 60 ± 11 years (range: 29-82), with a predominance of men 63.9% (n=101). The most common cardiovascular risk factors were tobacco (36.1%, n = 57), diabetes (48.1%, n =76), hypertension (55%, n = 87). Pre-procedural creatinine averaged 81.1 ± 47.3 µmol / L with extremes ranging from 39 to 600 µmol / L. The median Mehran risk score was 3.2 (range: 0- 15). The interventional cardiology act consisted of coronary angiography in 86.2% (n=136) of cases, coronary angioplasty in 2.5% (n=4) of cases. We used iohexol and iopromide in 57.6% (n=91) and 42.4% (n=67) of cases, respectively. The overall incidence of CMIN was 9.5% (n=9). The multivariable regression analysis identified 4 risk factors independently linked to the occurrence of CMIN which were Pre-existing renal failure (OR: 6.05, 95%CI [1.23-29.62], p = 0.026), anemia (OR: 0.043, CI [1.03-8.96], p = 0.043), the toxic dose of PC (OR: 4.7, CI [1.28-17.7], p=0.02), and at a Mehran score = 11 (OR: 3.7, CI [0.88-15.6], p=0.036). Conclusion: the most effective approach for CMIN is prevention, which focuses on addressing modifiable risk factors to minimize the risk especially in patients with pre-existing renal failure.

[Isolated laryngeal tuberculosis as an uncommon manifestation of extrapulmonary tuberculosis in adults: a case report]. / Tuberculose laryngée isolée de l'adulte: localisation extra pulmonaire exceptionnelle (à propos d'un cas).

Isolated laryngeal tuberculosis is rare and sometimes difficult to diagnose. It is the most common cause of laryngeal granuloma. We here report the case of a 58-year-old man, with no particular past medical history, hospitalized due to paroxysmal laryngeal dyspnea, dysphagia to solid foods and dysphonia evolving for 6 months without other associated signs. Laryngoscopic examination showed polyploid formation masking the glottic floor. Histological examination revealed epithelioid and gigantocellular granuloma, without caseous necrosis. Direct microscopic examination and culture were negative. The diagnosis of isolated laryngeal tuberculosis was made based on the endemicity in our country and the absence of other arguments in favor of another type of granulomatosis. Anti-tuberculosis therapy, combined with oral corticosteroids, was indicated based on the presence of severe upper airway edema and symptoms were resolved after 40 days of treatment.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits: Successful treatment for new and rare entity.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits is a new disorder with undefined treatment modalities. We propose cyclophosphamide-bortezomib-dexamethasone and autologous stem cell transplantation as a therapeutic protocol.

Nephrotic syndrome in elderly: Etiologies, management, and prognosis.

The elderly population has significantly increased in the world. Nephrotic syndrome (NS) is one manifestation of glomerular nephropathy in the elderly. The objective of our study is to determine NS particularities in the elderly and to identify the factors predicting progression to chronic end-stage renal disease (ESRD). This is a retrospective and descriptive study, carried out between January 1, 1975 and December 31, 2017. It includes participants aged 65 years old or over hospitalized for NS. A multivariate study was carried out and the dependent variable was the evolution to ESRD. We studied 115 patients with an average age of 71 ±5 years (65-83) and a sex ratio (male/female) of 1.7. Twenty-three percent of patients were diabetic. The median proteinuria was 4.7 g/L (3-19.5). NS was impure in 89.5% of patients. Renal biopsy was performed in 45 patients (39.13%). NS was secondary in 65.2% of cases mainly to amyloidosis (35.6%). Idiopathic nephropathy was dominated by membranous nephropathy (9.5%). Treatment was etiopathogenic in only 18 patients (15.6%). At the end of follow-up, 15.8% of patients achieved complete or partial remission and 56.6% progressed to ESRD. The multivariate study found as independent risk factors of progression to ESRD: uremia >17 mmol/L [adjusted odds ratio (aOR) = 33.2 (1.3-837.7); P <0.05],, phosphoremia ≥1.6 mmol/L [aOR = 22.1 (1.8-266.5); P <0.05], serum potassium ≥4.3 mmol/L (aOR = 24.7 (2.4, 251.5); P <0.01], extra-renal signs [aOR = 38.9 (2.4-634.3); P = 0.01], secondary nephropathy [aOR = 74 (3.1-1788.2); P <0.01] and membranoproliferative glomerulonephritis [aOR = 48 (1.4-1675.5); P <0.05]. The protective factors were hemoglobinemia ≥9.3 g/dL [aOR = 0.007 (0-0.2); P <0.01], kidneys well differentiated [0.032 (0.003-0.4); P<0.01] and treatment with two diuretics [aOR = 0.03 (0.00-30.4); P <0.01]. It is important to recognize the spectrum of kidney diseases in the elderly to improve the progression factors to ESRD.

End-stage renal disease at dialysis initiation: Epidemiology and mortality risks during the first year of hemodialysis.

Chronic kidney disease (CKD) treated by hemodialysis (HD) is a worldwide major public health problem. Its incidence is getting higher and higher, leading to an alarming social and economic impact. The survival of these patients is significantly low, especially during the first year of treatment. The purpose of our study was to identify the epidemiological and clinico-biological characteristics of patients at the HD initiation and to reveal the predictive factors of mortality at three months and one year of HD. This is a prospective, analytical, and descriptive study dealing with 229 patients with an end-stage renal disease (ESRD), followed up in the Nephrology Department of Charles Nicolle Hospital and La Rabta Hospital in Tunisia, that was started HD between January and June 2017. A multivariate logistic regression analysis allowed us to identify the independent predictors of mortality at three months and one year. The average age was 60.2 ± 15.3 years, with a gender ratio of 1.41. Seventy-eight percent of patients had more than two comorbidities, 59% had diabetes, and 88% had hypertension. Diabetic nephropathy was the leading etiology of kidney disease (48.9%), while 11% of nephropathies were of unknown etiology. Only 58% were early referred to a nephrologist. The average glomerular filtration rate at HD initiation was 6.06 ± 2.33 mL/min/1.73 m2. Hypocalcemia and hyperphosphatemia were noted, respectively, in 60.8% and 84.9% of cases. Anemia was objectified in 98.6% of cases. HD was started in an emergency in 56.8% of cases. One of the most urgent indications was acute pulmonary edema (APE) for 43.8% of patients. Only 10.5% of patients had functional arteriovenous fistula at the dialysis initiation. Patients were hemodialyzed one, two, or three sessions per week, respectively, in 23.2%, 26.6%, and 50.2% of cases. The crude mortality rate was 25% and 13% in, respectively, one year and three months of HD. On multivariate analysis, we identified heart failure and insufficient dialysis dose per week as predictive factors of mortality at the 1st year of HD. C-reactive protein more than 21 mg/L, insufficient dialysis per week, modified Charlson Comorbidity Index less than 6, and APE at the dialysis initiation were identified as predictive factors of three-month mortality. Despite the short period of study, this work revealed the alarming conditions of patients at HD initiation. This critical situation is due to the delay in CKD diagnosis, the late nephrologist referral, and the lack of preparation before HD initiation.

National Epidemiological Study about Hepatitis C Virus Infection among Dialysis Patients.

The World Health Organization estimates that 3% of the general population is infected with this virus. Hepatitis C remains the main viral infection in dialysis patients, and the severity of this infection is the risk of developing cirrhosis or hepatocarcinoma. We aim to determine the prevalence of hepatitis C in dialysis patients, to calculate the rate of hepatitis C virus (HCV) seroconversion, and to identify the risk factors for seroconversion. This is a nationwide multicenter observational study including all dialysis patients regardless of age and gender. Those with acute renal failure and vacationers were excluded from the study. We included 185 centers including 176 hemodialysis (HD) centers and nine peritoneal dialysis (PD) centers with a total number of patients at 11,238, a number of HCV-positive patients at 402, and a number of functional machines at 3139. The mean age of a patient was 55.6 years (range: 18-65), and sex ratio was 0.9. The prevalence of HCV-positive patients is 3.6%; it is higher in private centers with an average of 2.7 compared to 1.18 in public centers with a significant difference (P = 0.009). The prevalence of HCV-positive patients was significantly higher in HD centers compared to PD centers, in centers where the number of generators was >15 and when the number of patients per center is >70. One hundred and fifty-six patients seroconverted after dialysis, i.e., a prevalence of seroconversion at 1.3% with a mean delay of 6.052 ± 5.3 years. Our study shows a lower prevalence of HCV seroconversion than that reported in the literature; this requires a national survey to be carried out by homogenizing virological diagnostic kits and treating infected patients to eradicate this infection in dialysis patients.

Renal Thrombotique microangiopathy: An unusual renal involvement in Niemann-Pick disease type B.

Renal involvement in Niemann-Pick disease type B is very rare. Kidney check-up and renal biopsy should be performed in any patient presented with hypertension and kidney disease. Histology identifies the lesion, the prognosis, and guide treatment.

Acquired Bartter Syndrome in Primary Sjögren Syndrome.

Renal tubular involvement in Sjögren's syndrome (SS) often described with renal tubular acidosis, nephrogenic diabetes insipidus, or rarely with Fanconi syndrome. SS presenting with clinical features of Bartter's syndrome or Gitelman's syndrome is rare. We report a case of a female patient who presented an acquired Bartter syndrome with a primary SS.

Mycophenolate Mofetil-induced Oral Ulcerations in a Kidney Transplant Recipient.

INTRODUCTION: Mycophenolate Mofetil (MMF) is an immunosuppressive drug usually used in kidney transplants to prevent rejection. It has various adverse effects such as leucopenia, anemia, diarrhea but Mouth ulcers are rarely reported. METHOD: We present a case report of MMF-induced mouth ulcers in an African patient. CASE REPORT: A 41-year-old African-male patient has painful oral ulcers which developed 5 months after kidney transplantation. The immunosuppressive maintenance regimen comprised Steroids, Tacrolimus and MMF. RESULT: These ulcers were firstly related to a fungic or viral infection so the patient was prescribed Fluconazole and Aciclovir without any improvement. Then, Tacrolimus blood level was checked and it was in a therapeutic range. Finally, we decide to stop MMF and the ulcers healed quickly. DISCUSSION: Oral ulcers are frequently seen complications in immunosuppressant patient but are rarely described with MMF. These ulcers can become large and very painful and degrade patient's life quality. So when infections causes are excluded, we have to keep in mind that these ulcers can be a drug adverse effect.

Monoclonal gammopathy of renal significance with light-chain deposition disease in kidney transplantation.

Light-chain deposition disease (LCDD) reoccurs almost invariably after renal transplantation, leading to early graft loss. We report a case of LCDD with monoclonal gammopathy of renal significance diagnosed in the post-transplant period in a 28-year-old male and we discuss the diagnostic and therapeutic challenges in the clinical course.

Extensive sphenoid chordoma mimicking a prolactinoma.

The chordoma is a benign cartilaginous tumor whose sphenoidale localization is exceptional. This tumor has considerable difficulties of both diagnosis and treatment. We report the observation of a Tunisian adult who presented features of hypopituitarism set wrongly on account of a prolactinoma.

Prolonged fever and intra-cardiac thrombosis revealing Behçet's disease.

BACKGROUND: Prolonged fever (PF) is a challenging problem for physicians since it can be the first manifestation of a large variety of pathologies. Exceptionally, intra-cardiac thrombus (ICT) could explain PF and reveal Behçet's disease (BD). We are reporting a 45-year-old man with BD who has these unusual manifestations. CASE REPORT: A 45-year-old man presented with PF and inflammatory biological syndrome during a few months. Echocardiography showed an inhomogeneous and mobile mass in the left auricle. During his hospitalization, the patient had multiple oral aphtosis. The angioscanner showed a sacciform aneurysm of the coeliac trunk. The diagnosis of BD was retained and he was treated with high doses of steroids and cyclophosphamide with a favorable follow-up. CONCLUSION: The search for BD should be systematic in view of any suggestive manifestation of severe cardiovascular complications like ICT especially in a young adult man from a high endemicity region.

Clinical study on autosomal dominant polycystic kidney disease among North Tunisians.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, which usually manifests in adulthood. It is characterized by the development of multiple cysts in the kidneys and many other extrarenal manifestations. We aimed to determine the factors that contribute to the progression of ADPKD to end-stage renal disease (ESRD). In a retrospective multicentric study, we reviewed the records of 569 patients with ADPKD, hospitalized at a nephrology department or followed up at the outpatient department of university and regional hospitals, covering the north and center of the country, during the period 1969-2016. The mean age of the study patients was 48.54 ± 13.68 years and 14% were young adults (<40 years). There were 272 female and 297 male patients (sex ratio: male/female = 1.09). A family history of ADPKD was found in 43.7% of cases. Renal symptoms were dominated by loin pain, renal failure, hypertension, and hematuria, seen in, respectively, 51.9%, 48.2%, 29.1%, and 24.6% of the patients. The median serum creatinine level was 459 µmol/L (range: 47-2454), and hypertension had preceded the onset of ADPKD in 28.8% of cases. Extrarenal manifestations consisted of urologic complications (54.6%), liver cysts (43.5%), cardiac involvement (31.9%), cerebral aneurysms (12.9%), and gastrointestinal involvement (9.4%). ESRD occurred in 43.1% after a mean follow-up of 47 months (range: 0-384). Risk factors for poor renal prognosis were age >40 years (P = 0.009), hematuria (P = 0.034), hemoglobin >14 g/dL (P = 0.0013), high uric acid level (P = 0.001), and leukocyturia (P = 0.02). Death occurred in 59 cases (10.3%), mostly caused by infections (44.1%). In our study, ADPKD was lately diagnosed in most cases. Family screening is important, which will enable early detection and management of the complications associated with ADPKD.

Tubulointerstitial nephritis due to sarcoidosis: Clinical, laboratory, and histological features and outcome in a cohort of 24 patients.

Renal involvement is rare in systemic sarcoidosis. Among renal manifestations, tubulointerstitial nephritis (TIN) is the most commonly reported finding. We conducted the current study to investigate the clinical, laboratory, and histological features and to analyze the outcome of TIN due to sarcoidosis. We present a retrospective, single-center study of patients followed for sarcoidosis and presenting with TIN related to this systemic disease. Twenty-four patients were assessed (22 females/2 males). The mean age at diagnosis of TIN was 46.3 years. Extrarenal manifestations were dominated by thoracic involvement (95.8%), peripheral lymph nodes (54.2%), and skin lesions (33.3%). The mean proteinuria level was 0.68 g/24 h. Renal failure was diagnosed in 83.3% of cases with a median estimated glomerular filtration rate at 14.3 mL/min/1.73 m2. Nine patients presented with hypercalcemia and 12 patients with hypercalciuria. Renal biopsy was performed in 58.3% of cases. Six of the 14 patients presented with noncaseating granulomatous interstitial nephritis and eight with interstitial nephritis without granuloma. Granulomatous infiltration of renal parenchyma was complicated by vasculitis in two cases. Corticosteroid therapy was used in all patients. On follow-up analysis, four patients progressed to end-stage renal disease (ESRD) after a mean duration at 45.5 months. In the remaining patients, kidney function statistically significantly improved after one month of treatment compared to the time when the diagnosis was initially established (P = 0.031). We found that the predictive factors of progression to ESRD were multiorgan involvement (P = 0.032), advanced fibrosis F3 (P = 0.0006), and extensive interstitial granulomas (P = 0.007) and these were independently correlated with ESRD. Corticosteroid therapy seems to be effective in sarcoid TIN, but some degree of persistent renal failure is possible which can be predicted from both histologic findings and initial response to steroid therapy.

Simultaneous acute pancreatitis and angioedema associated with angiotensin-converting enzyme inhibitor.

Angiotensin-converting enzyme inhibitors (ACEI) are commonly prescribed drugs for blood pressure (BP) control and renal protection. The use of ACEI is not associated with an increased risk of acute pancreatitis and ACEI-induced angioedema is rare. A 36-year-old woman presented with vomiting, headache, and aphasia. Her BP was 220/100 mm Hg. urine analysis revealed proteinuria (2+), hematuria (3+). Serum creatinine level was at 1125 µmol/L. She had anemia with 6.1 g/dL of hemoglobin and thrombocytopenia (61,000/mm3). Renal histology revealed lesions of thrombotic microangiopathy. The diagnosis of atypical hemolytic uremic syndrome was made by the complement factor I deficiency. Plasma exchanges could not be done. She was placed on peritoneal dialysis for renal insufficiency. We introduced an ACE (captopril) for the treatment of high BP. Twelve-hours after taking the first dose, she experienced severe epigastric pain and two episodes of vomiting. Serum lipase was 560 IU/L, and abdominal computed tomography showed Stage B pancreatitis. Twenty-four hours later, the patient developed marked edema of the neck region without dyspnea or dysphonia. Cervical ultrasound revealed the infiltration of the subcutaneous tissues. Captopril was stopped with the progressive disappearance of the edema. Serum lipase was 350 IU/L and then normalized at the end of the 4th day. Clinicians should be careful about widely used drugs and their side effects. ACEI can cause potentially life-threatening complications such as angioedema and acute pancreatitis. Possibly, there could be a common mechanism for the onset of pancreatitis and angioedema under ACEI.

Renal amyloidosis in ankylosing spondylitis: A monocentric study and review of literature.

Secondary renal amyloidosis (RA) is the most common type of renal involvement in ankylosing spondylitis (AS). We assessed the epidemiologic and clinico-biological profile of AS patients with RA, to analyze treatment modalities and prognostic aspects, and to determine predictive factors of RA during AS. This was a retrospective study including 13 cases of RA among 212 cases who presented with AS, during the period from 1978 to 2006. The median age of the patients at the time of diagnosing AS was 47 years (range: 19-67). There were 11 males and two females. RA onset was diagnosed after a mean follow-up of 144.6 months (range: 10-505) from the AS diagnosis. We noted erosive peripheral arthritis, lumbar stiffness with bamboo spine, and coxitis in 23.1%, 76.9%, and 30.8% of cases, respectively. Nephrotic syndrome was found in eight patients (61.5%). At the time of diagnosing RA, six patients had renal failure. Amyloid deposits were histologically proven by salivary gland biopsy in six cases (46.1%) and by renal biopsy in seven cases (53.8%). Four patients received a long-course treatment with colchicine but with a good outcome only in two cases. In our series, AS was more severe among patients with RA. Four predictive factors of RA were identified: smoking (P = 0.04), erosive peripheral arthritis (P = 0.002), bamboo spine (P = 0.001), and biologic indicators of inflammation (P = 0.0001). High erythrocyte sedimentation rate was identified as the only independent risk factor of RA during AS (P = 0.0001). Renal function as well as urinalysis should be monitored at regular intervals to detect early renal involvement during AS.

[Renal prognosis of IgA vasculitis nephritis in adult patients: a monocentric study of 25 cases]. / Pronostic rénal de la néphropathie des vascularites à IgA de l'adulte: étude monocentrique, à propos de 25 cas.

IgA vasculitis nephritis affects the prognosis of this disease in adult patients. This study aimed to examine the clinical characteristics of this renal involvement in adults and to identify factors influencing renal prognosis. We conducted a retrospective monocentric study of patients with histologically confirmed IgA vasculitis nephritis (rheumatoid purpura) (EULAR classification criteria) with renal involvement classified according to Pillebout classification. We analyzed renal survival and identified the factors influencing renal prognosis. Twenty-five patients were included (sex ratio M/F = 2.57), their average age at diagnosis of rheumatoid purpura was 35,76 years. Purpura was diagnosed in 100% of cases, with articular involvement in 28% of cases. Renal failure was identified in 44% of cases. The most common histological classification was IgA vasculitis nephritis (class II). Clinical remission was observed in 44% of cases and an evolution toward chronic renal failure (end-stage renal disease) in 36% of cases. Renal survival at 195 months was 57%. The identified prognostic factors were digestive involvement (p = 0.022), early renal failure (p = 0.0004), glomerular classification (P=0,001) and the severity of the histological lesions, renin-angiotensin system blocker treatment (p = 0.01) and plasma exchanges (p = 0.03). Our study shows that renal involvement during IgA vasculites can be relatively severe with poor renal prognosis. The identification of clinical and histological prognostic factors may be useful as guidance for the development of prospective therapeutic studies.

Factors associated with relapse of lupus nephritis: A single center study of 249 cases.

This is a retrospective cohort study over 20 years (1990-2013) that included all patients with biopsy-proven lupus nephritis (LN) followed up at our nephrology department. We aimed to determine the clinicobiologic predictors of flare-up of LN. Flare was defined as an increase in systemic lupus erythematosus (SLE) disease activity index (SLEDAI) score of at least four points. Clinical manifestations and laboratory parameters were assessed and the SLEDAI score was determined for each patient. We included patients with SLE who fulfilled at least four of the American College of Rheumatology criteria for the classification of SLE. A total of 249 patients including 227 females and 22 males with a median age at diagnosis of 34.32 years (range 16-69) were studied. The mean follow-up duration was 122.4 ± 27 months. Renal symptoms included hypertension in 40%, nephrotic syndrome in 30%, and renal failure in 69.4% of the cases. Class IV and class III nephritis (ISN/RPS) were observed in 44.9% and 24% of the patients, respectively. On univariate analysis, flare predictors were age <30 years (P = 0.02), lymphocytopenia (P = 0.002), the presence of diffuse proliferative LN (P = 0.009), and discontinuation of immunosuppressive therapy (P = 0.004). Our study suggests that these markers should be monitored routinely as prognostic parameters in SLE to characterize patients who are at risk and who should be followed more closely.

Acute kidney injury with granulomatous interstitial nephritis and vasculitis revealing sarcoidosis.

Sarcoidosis is an inflammatory disease that affects mostly the lungs and lymph glands. Renal involvement is rare and especially vasculitis. We report a case who presented an acute kidney failure and had sarcoidosis with vasculitis and nodular splenic involvement. A 35-year-old woman presenting a Lofgren syndrome was hospitalized for acute renal failure with cervical lymphadenopathy without other clinical findings. Laboratory data disclosed elevated angiotensin converting enzyme serum level. Abdominal ultrasound showed a multinodular spleen. Renal histology revealed granulomatous interstitial nephritis with necrotizing vasculitis. Outcome was favorable after the institution of high dose corticosteroids along with cyclophosphamide. Renal involvement is rare in sarcoidosis. However, the diagnostic delay should be avoided to improve the outcome.

Nondiabetic renal disease in patients with type 2 diabetes.

Diabetic nephropathy (DN) is one of the major complications of type 2 diabetes mellitus (T2DM). The diagnosis of DN is mostly clinical. Kidney biopsy is indicated only if nondiabetic renal disease (NDRD) is suspected. This study is aimed to assess the prevalence of NDRD and to determine predictor and prognostic factors of DN, NDRD. It was a retrospective analytic study including T2DM patients in whom renal biopsies were performed at our department from 1988 to 2014. Seventy-five patients were included. Mean age was 52.7 years with sex ratio at 1.56. Renal biopsy findings were isolated NDRD in 33 cases, NDRD superimposed on DN in 24 cases, and isolated DN in 18 cases. Most common NDRD found were focal segmental glomerulosclerosis (21%) and membranous nephropathy (19%). Multivariate analysis showed that the absence of ischemic heart disease [odds ratio (OR) = 0.178, 95% confidence interval (CI) = 0.041-0.762], absence of peripheral vascular disease (OR = 0.173, 95% CI = 0.045-0.669), and presence of hematuria (OR = 7.200, 95%CI = 0.886-58.531) were independent predictors of NDRD. 24 patients reached end-stage renal disease 55% in DN group, 16% in DN associated to NDRD group, and 30% in NDRD group. The prevalence of NDRD found in our study confirmed usefulness of renal biopsy in patients with T2DM, especially in those without degenerative complications, hypertension, and insulin therapy.