Adequate corticomedullary differentiation is suggestive of no chronic parenchymal impairment, and is a frequent finding in acute renal failure (option 4 correct). A family history of nephropathy could indicate the existence of a hereditary disorder (incorrect option 2). Small kidneys and hyperphosphatemia are features of chronic kidney disease (option 1 and 3 incorrect).

Adequate corticomedullary differentiation is suggestive of no chronic parenchymal impairment, and is a frequent finding in acute renal failure ([HIDDEN]). A family history of nephropathy could indicate the existence of a hereditary disorder ([HIDDEN]). Small kidneys and hyperphosphatemia are features of chronic kidney disease ([HIDDEN]).

A 48-year-old patient referred to the nephrology department for an estimated glomerular filtration rate (eGFR) of 32 ml/min/1.72 mL/min/1.72 mL. Which of the following data would NOT suggest chronic kidney disease?

Good ultrasound differentiation of renal cortex and medulla.

High chronic nephropathy detection yield in CKD subjects identified by the combination of albuminuria and estimated GFR.

Epidemiological studies have shown that the burden of chronic kidney disease (CKD) is huge. CKD is a non-specific diagnosis, however, and it is hard to say which renal disorders comprise the body of CKD diagnosed on the strength of the combination of albuminuria and estimated glomerular filtration rate (eGFR) in epidemiological studies, or just how efficient such studies are in detecting chronic nephropathies. The INCIPE study identified 524 CKD cases (using the K/DOQI definition based on albuminuria and eGFR) in a random sample of 4000 Italians >40 years old, 262 of whom were randomly chosen to be investigated in order to confirm their CKD and complete a diagnostic workup. We a priori defined diagnostic algorithms for 14 renal conditions based on personal family history, medical records, urine tests, kidney ultrasound with colour-Doppler and other tests. Among the subjects whose CKD was confirmed, a diagnosis of chronic nephropathy was reached in 68% of cases recognized as having either a specific (38%) or an undetermined (30%) kidney disease. Almost 50% of subjects with a specific chronic nephropathy had a diabetic or vascular renal disease. Abnormalities consistent with a chronic nephropathy were found in 50, 68, 70 and 100% of subjects with CKD Stages 1, 2, 3 and 4, respectively. Lone low eGFR and lone microalbuminuria were observed in 20 and 12%, respectively. In Caucasians >40 years old with a confirmed CKD condition, (i) an impressive 68% of subjects have an underlying chronic nephropathy, so eGFR and albuminuria are very efficient in detecting renal diseases; (ii) in 32%, the only disclosed renal abnormalities were a glomerular filtration rate <60 mL/min/1.73 m(2) or microalbuminuria; follow-up studies are needed to clarify whether these abnormalities do really identify a chronic nephropathy or just a cardiovascular risk condition.

Mesoamerican nephropathy

Suspected disease: Estimated GFR (eGFR) < 60 ml/min/1.73m2 Absence of diabetes, hypertension, autoimmune disease, glomerular disease, congenital kidney disease, obstructive kidney disease as a clear cause of kidney disease (these comorbidities may be present but cannot account for disease development) Residing in a hotspot region Proteinuria < 2g/24h or 2g/g urine creatinine Likely disease: All of the above, plus eGFR < 60 ml/min/1.73m2 on 3 month or longer repeat measurement Relative hypokalemia and/or hyperuricemia Kidney ultrasound with loss of corticomedullary differentiation or bilateral small kidney size, without cystic disease or large stone burden Kidney biopsy showing primary tubulointerstitial disease without alternative cause of kidney disease in evidence

Renal Morphology, Clinical Findings, and Progression Rate in Mesoamerican Nephropathy.

Mesoamerican nephropathy (MeN) is a chronic kidney disease affecting rural inhabitants in Central America. We have previously described the renal morphology in 8 patients from El Salvador. To confirm the renal pathology, we have studied kidney biopsies from patients with MeN in Nicaragua. Follow-up urine and blood samples from both biopsy studies were collected to investigate the natural history. Case series. In the kidney biopsy study, 19 male sugarcane workers in Nicaragua with suspected MeN were investigated with questionnaires, kidney biopsies, and blood and urine analysis. Inclusion criteria were age 20 to 65 years and plasma creatinine level of 1.13 to 2.49mg/dL or estimated glomerular filtration rate (eGFR) of 30 to 80mL/min/1.73m<sup2</sup. Exclusion criteria were proteinuria with protein excretion > 3g/24 h, uncontrolled hypertension, diabetes mellitus, or other known kidney disease. In the follow up-study, blood and urine from the kidney biopsy study in Nicaragua (n=18) and our previous biopsy study of MeN cases in El Salvador (n=7) were collected 1 to 1.5 and 2 to 2.5 years after biopsy, respectively. Renal morphology, clinical, and biochemical characteristics, change in eGFR per year. eGFR was calculated using the CKD-EPI creatinine (eGFR<subcr</sub), cystatin C (eGFR<subcys</sub), and creatinine-cystatin C (eGFR<subcr-cys</sub) equations. In the kidney biopsy study, participants had a mean eGFR<subcr</sub of 57 (range, 33-96) mL/min/1.73m<sup2</sup. 47% had low plasma sodium and 21% had low plasma potassium levels. 16 kidney biopsies were representative and showed glomerulosclerosis (mean, 38%), glomerular hypertrophy, and signs of chronic glomerular ischemia. Mild to moderate tubulointerstitial damage and mostly mild vascular changes were seen. In the follow up-study, median duration of follow-up was 13 (range, 13-27) months. Mean change in eGFR<subcr</sub was -4.4±8.4 (range, -27.7 to 10.2) mL/min/1.73m<sup2</sup per year. Most patients had stopped working with sugarcane cultivation. 3 biopsy specimens had 4 or fewer glomeruli. This study confirms the renal morphology of MeN: chronic glomerular and tubulointerstitial damage with glomerulosclerosis and chronic glomerular ischemia. Follow-up data show that eGFRs, on average, deteriorated.

Assessment of kidney function

The most relevant assessments in a renal ultrasound are renal sizes, echogenicity and any signs of hydronephrosis. Renal enlargement usually indicates diabetic nephropathy, focal segmental glomerular sclerosis or myeloma. Renal atrophy suggests longstanding chronic renal disease. Chronic kidney disease stages Risk factors for kidney disease include diabetes, high blood pressure, family history, older age, ethnic group and smoking. For most patients, a GFR over 60 (mL/min)/(1.73 m2) is adequate. But significant decline of the GFR from a previous test result can be an early indicator of kidney disease requiring medical intervention. The sooner kidney dysfunction is diagnosed and treated the greater odds of preserving remaining nephrons, and preventing the need for dialysis.

Glomerular filtration rate

Chronic kidney disease stages Risk factors for kidney disease include diabetes, high blood pressure, family history, older age, ethnic group and smoking. For most patients, a GFR over 60 mL/min/1.73m2 is adequate. But significant decline of the GFR from a previous test result can be an early indicator of kidney disease requiring medical intervention. The sooner kidney dysfunction is diagnosed and treated the greater odds of preserving remaining nephrons, and preventing the need for dialysis.

Glomerular filtration rate

The severity of chronic kidney disease (CKD) is described by six stages; the most severe three are defined by the MDRD-eGFR value, and first three also depend on whether there is other evidence of kidney disease (e.g., proteinuria): 0) Normal kidney function – GFR above 90 mL/min/1.73 m2 and no proteinuria 1) CKD1 – GFR above 90 mL/min/1.73 m2 with evidence of kidney damage 2) CKD2 (mild) – GFR of 60 to 89 mL/min/1.73 m2 with evidence of kidney damage 3) CKD3 (moderate) – GFR of 30 to 59 mL/min/1.73 m2 4) CKD4 (severe) – GFR of 15 to 29 mL/min/1.73 m2 5) CKD5 kidney failure – GFR less than 15 mL/min/1.73 m2 Some people add CKD5D for those stage 5 patients requiring dialysis; many patients in CKD5 are not yet on dialysis. Note: others add a "T" to patients who have had a transplant regardless of stage.

[Estimation of glomerular filtration rate in primary care: prevalence of chronic kidney disease and impact on referral to nephrology].

Data were collected in 18.922 patients attending Primary Care Centers in Alcañiz (Spain), mean age 59,96 +/- 17 years, 42,9 % males and 57,1 % females. The prevalence of eGFR was: stage 3 (30-59 ml/min/1,73 m2) 15,7 %; stage 4 (15-29 ml/min/1,73 m2) 0,6 %; stage 5 no dialysis (GFR < 15 ml/min/1.73 m2) 0,1 %. This prevalence increased with age and 32 % of patients attending Primary Care services over 65 years presented a eGFR < 60 ml/min/1,73 m2. Of the total patients with eGFR < 60 ml/min/1,73 m2, 26 % had normal serum creatinine levels. Protocol implementation could implied for the Renal Unit an increase in the number of patients, specially the oldest ones. This study documents the substantial prevalence of significantly abnormal renal function among patients at Primary Care level and the importance of Primary Care collaboration in their early identification and appropriate management.

Glomerular filtration rate

Normal ranges The normal range of GFR, adjusted for body surface area, is 100–130 average 125 mL/min/1.73m2 in men and 90–120 ml/min/1.73m2 in women younger than the age of 40. In children, GFR measured by inulin clearance is 110 mL/min/1.73 m2 until 2 years of age in both sexes, and then it progressively decreases. After age 40, GFR decreases progressively with age, by 0.4–1.2 mL/min per year. Decreased GFR A decreased renal function can be caused by many types of kidney disease. Upon presentation of decreased renal function, it is recommended to perform a history and physical examination, as well as performing a renal ultrasound and a urinalysis. The most relevant items in the history are medications, edema, nocturia, gross hematuria, family history of kidney disease, diabetes and polyuria. The most important items in a physical examination are signs of vasculitis, lupus erythematosus, diabetes, endocarditis and hypertension.

Chronic kidney disease

Chronic kidney disease (CKD) is a type of kidney disease in which there is gradual loss of kidney function over a period of months to years. Initially there are generally no symptoms; later, symptoms may include leg swelling, feeling tired, vomiting, loss of appetite, and confusion. Complications include an increased risk of heart disease, high blood pressure, bone disease, and anemia. Causes of chronic kidney disease include diabetes, high blood pressure, glomerulonephritis, and polycystic kidney disease. Risk factors include a family history of chronic kidney disease. Diagnosis is by blood tests to measure the estimated glomerular filtration rate (eGFR), and a urine test to measure albumin. Ultrasound or kidney biopsy may be performed to determine the underlying cause. Several severity-based staging systems are in use.

Chronic kidney disease

The glomerular filtration rate (GFR) is derived from the serum creatinine and is proportional to 1/creatinine, i.e. it is a reciprocal relationship:the higher the creatinine, the lower the GFR. It reflects one aspect of kidney function: how efficiently the glomeruli - the filtering units - work. Normal GFR is 90-120 mLs/min. The units of creatinine vary from country to country. But since the glomeruli make up <5% of the mass of the kidney, the GFR does not indicate all aspects of kidney health and function. This can be done by combining the GFR level with the clinical assessment of the person, including fluid status, and measuring the levels of hemoglobin, potassium, phosphate and parathyroid hormone (PTH).

Phosphate nephropathy

Diagnosis Phosphate nephropathy can be diagnosed via different types of assessment, most of which are also used to detect acute kidney injury and chronic kidney disease. Most phosphate nephropathy incidents are diagnosed weeks or months after taking OSP, due to its clinical silence. For example, these assessments include the measurement of serum phosphorus with an elevation of more than 3 mmol/L, the finding of an elevated serum creatinine level and a decrease in glomerular filtration rate (GFR), urine microscopy for crystallization detection, the image of calcium phosphate crystals deposited through CT scanning, urinalysis, renal biopsy specimens with histochemical staining for calcium phosphate. These assessments are generally carried out within the laboratory environment, in which longer waiting time is required to attain the results.

Glomerular filtration rate

Modification of Diet in Renal Disease (MDRD) formula Another formula for calculating the GFR is the one developed by the Modification of Diet in Renal Disease Study Group. Most laboratories in Australia, and the United Kingdom now calculate and report the estimated GFR along with creatinine measurements and this forms the basis of diagnosis of chronic kidney disease. The adoption of the automatic reporting of MDRD-eGFR has been widely criticised. The most commonly used formula is the "4-variable MDRD", which estimates GFR using four variables: serum creatinine, age, ethnicity, and gender. The original MDRD used six variables with the additional variables being the blood urea nitrogen and albumin levels. The equations have been validated in patients with chronic kidney disease; however, both versions underestimate the GFR in healthy patients with GFRs over 60 mL/min. The equations have not been validated in acute renal failure. For creatinine in μmol/L: For creatinine in mg/dL:

Assessment of kidney function

The severity of chronic kidney disease (CKD) is described by six stages; the most severe three are defined by the MDRD-eGFR value, and first three also depend on whether there is other evidence of kidney disease (e.g., proteinuria): 0) Normal kidney function – GFR above 90 (mL/min)/(1.73 m2) and no proteinuria 1) CKD1 – GFR above 90 (mL/min)/(1.73 m2) with evidence of kidney damage 2) CKD2 (mild) – GFR of 60 to 89 (mL/min)/(1.73 m2) with evidence of kidney damage 3) CKD3 (moderate) – GFR of 30 to 59 (mL/min)/(1.73 m2) 4) CKD4 (severe) – GFR of 15 to 29 (mL/min)/(1.73 m2) 5) CKD5 kidney failure – GFR less than 15 (mL/min)/(1.73 m2) Some people add CKD5D for those stage 5 patients requiring dialysis; many patients in CKD5 are not yet on dialysis. Note: others add a "T" to patients who have had a transplant regardless of stage.

Diabetic nephropathy

It is recommended that diabetics have their albumin levels checked annually, beginning immediately after a diagnosis of type 2 diabetes and five years after a diagnosis of type 1 diabetes. Medical imaging of the kidneys, generally by ultrasonography, is recommended as part of a differential diagnosis if there is suspicion of urinary tract obstruction, urinary tract infection, kidney stones or polycystic kidney disease. Conformation kidney biopsy should only be performed if non-diabetic kidney disease is suspected. Urine analysis in patients with diabetic kidney disease is often bland. In cases of severely increased microalbuminuria, hematuria might be present. fat bodies might be present in patients who develop nephrotic-range proteinuria. Staging To stage the degree of damage in this (and any) kidney disease, the serum creatinine is determined and used to calculate the estimated glomerular filtration rate (eGFR). Normal eGFR is equal to or greater than 90ml/min/1.73 m2.

Assessment of kidney function

There are several different techniques used to calculate or estimate the glomerular filtration rate (GFR or eGFR). The above formula only applies for GFR calculation when it is equal to the Clearance Rate. The normal range of GFR, adjusted for body surface area, is 100–130 average 125 (mL/min)/(1.73 m2) in men and 90–120 (mL/min)/(1.73 m2) in women younger than the age of 40. In children, GFR measured by inulin clearance is 110 (mL/min)/(1.73 m2) until 2 years of age in both sexes, and then it progressively decreases. After age 40, GFR decreases progressively with age, by 0.4–1.2 mL/min per year. Estimated GFR (eGFR) is now recommended by clinical practice guidelines and regulatory agencies for routine evaluation of GFR whereas measured GFR (mGFR) is recommended as a confirmatory test when more accurate assessment is required.

Glomerular filtration rate

A urinalysis is helpful even when not showing any pathology, as this finding suggests an extrarenal etiology. Proteinuria and/or urinary sediment usually indicates the presence of glomerular disease. Hematuria may be caused by glomerular disease or by a disease along the urinary tract. The most relevant assessments in a renal ultrasound are renal sizes, echogenicity and any signs of hydronephrosis. Renal enlargement usually indicates diabetic nephropathy, focal segmental glomerular sclerosis or myeloma. Renal atrophy suggests longstanding chronic renal disease. Chronic kidney disease stages

Autosomal dominant polycystic kidney disease

Prognosis In ADPKD patients, gradual cyst development and expansion result in kidney enlargement, and during the course of the disease, glomerular filtration rate remains normal for decades before kidney function starts to progressively deteriorate, making early prediction of renal outcome difficult. The CRISP study, mentioned in the treatment section above, contributed to build a strong rationale supporting the prognostic value of total kidney volume (TKV) in ADPKD; TKV (evaluated by MRI) increases steadily and a higher rate of kidney enlargement correlated with accelerated decline of GFR, while patient height-adjusted TKV (HtTKV) ≥600 ml/m predicts the development of stage 3 chronic kidney disease within 8 years.

Diabetic nephropathy

Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is one of the leading causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) globally. Protein loss in the urine due to damage to the glomeruli may become massive, and cause a low serum albumin with resulting generalized body swelling (edema) and result in the nephrotic syndrome. Likewise, the estimated glomerular filtration rate (eGFR) may progressively fall from a normal of over 90 ml/min/1.73m2 to less than 15, at which point the patient is said to have end-stage renal disease. It usually is slowly progressive over years.

[Chronic kidney disease in the source documentation of the outpatient clinic Department of Nephrology. Part II. Comparison of the three different methods of glomerular filtration rate estimation].

The aim of the study was to compare three methods of GFR estimation as simplified MDRD formula, Cockcroft-Gault formula and 24 hour urine collection used in evaluation of kidney function. The study was conducted at the outpatient clinic and enclosed 1183 patients aged between 17 and 98 years (mean 64.7) with creatinine level >120 micromol/l and/or creatinine clearance <90 ml/min/1.73 m2, described in detail in part I. After calculation we obtained different mean GFR values adequately to the method: 38.4 +/- 15.13 ml/min/1.73 m2 (simplified MDRD formula), 44.51 +/- 20.59 ml/min/1.73 m2 (Cockcroft-Gault formula) and 45.63 +/- 25.55 ml/min/1.73 m2 (24-h urine collection). Results of the GFR assessment were different according to the applied method of calculation. The smallest data dispersion was observed in GFR values calculated based on abbreviated MDRD formula and the highest when obtained based on to the 24-hour urine collection. The GFR values obtained based on 24 hour urine collection showed positive correlations with BMI (p<0.01), hemoglobine (p<0.01), hematocrite (p<0.01), diastolic blood pressure (p=0.01), albumin (p=0.041), iron (p=0.03), AIAT activity (p=0.01), and negative with age (p<0.01), phosphate (p<0.01), alkaline phosphatase activity (p=0.039), parathormone (p=0.03), potassium (p<0.01) and magnesium (p<0.01). In the group of patients with GFR values below 30 ml/min in comparison with patients with GFR values above 30 ml/min, in all three methods of GFR estimation it was shown significantly higher values of phosphate, potassium, age, and lower hemoglobin, hematocrite. It was shown also in the group with GFR below 30 ml/min values estimated based on Cockcroft-Gault formula and 24 hour urine collection significantly lower BMI.

[A study of serum phosphorus and renal phosphate excretion in children of different age groups].

To further elucidate the data of high serum phosphorus concentration reported for foreign children, this study compared the values of serum phosphorus concentration in ethnic Chinese children with foreigners' results, and investigated the potential causes of high serum phosphorus concentration. This study included 33 healthy term male neonates from 2-3 days to 5-7 days old, 1,094 children of 6-18 years old (elementary school-senior high school) and 62 adults. A total of 1,189 persons were studied. Value of serum phosphorus concentration showed no significant difference between boys and girls, and no age dependency; there was notable change in serum phosphorus concentration in growing children of different ages. The mean values of serum phosphorus concentration of neonates aged 2-3 days and 5-7 days (7.20 mg/dl and 7.65 mg/dl, respectively) were the highest; boys aged 6-11 years 5.15-5.50 mg/dl and girls aged 6-11 years 5.14-5.28 mg/dl were the second; boys aged 12-18 years 4.31-4.94 mg/dl and girls aged 12-18 years 4.44-4.96 mg/dl were the lowest. These findings are similar to the conclusions of foreign reports that the older the subjects of the study, the less their serum phosphorus concentration. The maximal transport rates of tubular phosphate reabsorption were determined from a Walton-Bijvoet nomogram using the side-rule method they recommend. The renal phosphate threshold concentration of neonates aged 2-3 days 8.41 mg/100 ml GFR and 5-7 days 7.76 mg/dl GFR was also the highest; boys aged 6-11 years 5.84-6.32 mg/dl GFR and girls aged 6-11 years 5.82-6.10 mg/dl GFR and 5.44-6.10 mg/dl GFR was the second; adult males 3.51 mg/dl GFR and adult females 3.62 mg/dl GFR was the lowest. Increased intestinal absorption of phosphorus, low GFR and low clearance of phosphorus might be the contributing factors to cause high serum phosphorus concentration. Although high renal phosphate threshold capacity is important, increased absorption of phosphorus by G-I tract seems to be another factor in accordance with the need of phosphorus of the growing body cells.

Renal Association

The Renal Association established the UK Renal Registry (UKRR) in 1995. The UKRR team manage data collection, analysis and reporting on approximately 8,000 new patients, 67,000 existing patients on RRT and on about 500,000 patients with an AKI each year. Data collated from renal centres and hospital laboratories is used to improve the care of patients with kidney disease across the UK. In 2005 the association published, together with the RCP of London, national guidelines on the diagnosis and management of chronic kidney disease (CKD), which led to the routine reporting of the estimated glomerular filtration rate (eGFR) by most National Health Service laboratories.

[Chronic kidney disease in the source documentation of the outpatient clinic Department of Nephrology. Part I. Causes of renal failure and characteristics of the studied population].

During the last years the incidence of chronic kidney disease (CKD) is permanently increasing and has become a global social and economical problem in the world as well as in Poland. The aim of the study was the retrospective analysis of medical records of patients with renal failure under supervision at the outpatient clinic, Department of Nephrology, University Hospital in Cracow. The study population enclosed 1183 patients (640 men and 543 women) aged between 17 and 98 years (mean 64.7) with creatinine concentration >120 micromol/l and/or creatinine clearance <90 ml/min/1.73 m2. Hemoglobin, iron, creatinine, urea, sodium, potasium, calcium, phosphate, magnesium, PTH, uric acid, albumin, total protein, bilirubin, glucose, total cholesterol, LDL and HDL cholesterol, triglicerydes concentration and values of hematocrite, MCV, HbA1, as well as alkaline phosphatase, AspAT, AIAT activity were estimated based on standard laboratory methods. Creatinine clearances were evaluated based on 3 different methods: simplified MDRD formula, Cockcroft-Gault formula and 24-h urine collection. Mean creatinine concentration in the studied population was 172.8 micromol/l (1.95 mg/dl). Hypertension was diagnosed in 65% of patients. In spite of treatment, more than half of the patients (51.9%) have increased systolic blood pressure and above 1/3 (35%) increased diastolic blood pressure. Mean hemoglobin concentration was 13.02 g/dl; more than 12% of patients had decreased hemoglobin below 11 g/dl. Mean values of parameters discovering calcium-phosphate metabolism were: calcium--2.33 mmol/l, phosphate--1.23 mmol/l and parathormon--169.3 pg/ml. Increased value of total serum cholesterol level was noted more than half of the patients (56.5%). Significant positive correlations were found between GFR calculated based on Cockcroft-Gault formula and BMI, hemoglobin, hematocrite, serum iron, diastolic blood pressure, total and LDL serum cholesterol, triglicerydes level, as well as AIAT activity and % values of HbA1c and negative with age, serum potassium, phosphorus, PTH and uric acid.

Assessment of serum electrolytes and kidney function test for screening of chronic kidney disease among Ethiopian Public Health Institute staff members, Addis Ababa, Ethiopia.

Chronic kidney disease (CKD), which is characterized by its asymptomatic nature until an end stage, is one of the most common public health problems in the world. Thus, a regular checkup, especially for those individuals with high risk groups is inevitably important, and the screening has been done with laboratory findings. However, in developing countries, including Ethiopia screening for CKD are rarely done, and it is becoming common to hear sudden death from the kidney failure. Therefore, we aimed to screen serum electrolyte levels and estimated glomerular filtration rate (eGFR) among Ethiopian Public Health Institute (EPHI) staff members for an early detection of CKD and to identify the factors associated with it. A cross-sectional study was conducted from July 1 to October 28, 2018 among EPHI staff members. The level of serum creatinine and electrolytes were measured using COBAS 6000 analyzer. Then, eGFR was calculated using MDRD and CKD-EPI equations. Data analysis were done using SPSS version 20, and the factors associated with the outcome variable were assessed using logistic regression. P values < 0.05 were considered as statistically significant. This study found that 3.6 and 1.9% of the study participants were at CKD stage II by MDRD and CKD-EPI equations, respectively. Out of the total study participants, 9.5% had hyperkalemia (serum potassium level > 5.0 mmol/L) and 8.5% had hypocalcemia (serum calcium level < 2.15 mmol/L). An older age (P = 0.006), high BMI (P = 0.045) and previous history of CVDs (P = 0.033) were found to be significantly associated factors with reduced glomerular filtration rate. Nine percent of the study participants were obese, 6.1% had family history of kidney failure, 18% self-reported history of hypertension, 3.4% diabetic and 5.3% had CVDs. About 51.2% of the study participants were males, and the majorities, (66%) of the study participants were found to be alcohol consumers. The prevalence of a stage II kidney disease was relatively low and none of the participants was under serious kidney disease (GFR < 60 mmol/min/1.73m<sup2</sup). An older age, high BMI and previous history of CVDs were significantly associated with reduced GFR. Hyperkalemia and hypokalemia were the major electrolyte disorders in the study participants.

[One-year follow-up of renal function in endemic nephropathy families].

Endemic nephropathy is familial, chronic tubulointerstitial disease with an insidious onset and asymptomatic, slow progressive course. The present study was undertaken with the aim to find out whether new persons with renal disorders can be detected among members of endemic families in the village of Sopić (Kolubara River region, Serbia). The study involved 44 members of five endemic families without history of renal disorders. Objective survey and laboratory analyzes that enabled determination of kidney functions (creatinine clearance, proteinuria, urine specific gravity and osmolality, fractional sodium excretion (FENa), the rate of tubular phosphate reabsorption (TRP), urine N-acetil-D-glycosaminidase and intestinal alkaline phosphatase) were done in all examined persons three times during the 6-month intervals. At the first examination, hypertension was detected in 23 (52%) person, decreased creatinine clearance in two and proteinuria in 10 persons included in the study. In addition, proteinuria and tubular disorders were detected in 6, hypertension, proteinuria and/or tubular disorders in 9 persons. The analysis of the results obtained by three check-ups undertaken during one year showed that proteinuria and tubular disorders appeared intermittently in half of the examined endemic family members. All persons with detected renal disorders required further examination in order to establish accurate diagnosis of renal disease. Three check-ups performed at six-month intervals in the members of five endemic families detected various renal disorders including renal hypofunction. Regular systematic check-ups of endemic families could enable early detection of the disease and early initiation of measures for slowing down chronic renal disease progression.

Dialysis

Chronic indications Chronic dialysis may be indicated when a patient has symptomatic kidney failure and low glomerular filtration rate (GFR < 15 mL/min). Between 1996 and 2008, there was a trend to initiate dialysis at progressively higher estimated GFR, eGFR. A review of the evidence shows no benefit or potential harm with early dialysis initiation, which has been defined by start of dialysis at an estimated GFR of greater than 10 ml/min/1.732. Observational data from large registries of dialysis patients suggests that early start of dialysis may be harmful. The most recent published guidelines from Canada, for when to initiate dialysis, recommend an intent to defer dialysis until a patient has definite kidney failure symptoms, which may occur at an estimated GFR of 5–9 ml/min/1.732. Dialyzable substances

[Secondary hyperparathyroidism as a cause of delayed functioning of renal graft. Reports of two cases].

Parathormone (PTH) exerts vasomodulatory effect. In patients with severe hyperparathyroidism (HPTx) post transplant (Tx) PTH level decreases slowly and this could be a reason of delayed graft function. Case 1: 19 years old female; 2 years of CAPD-renal Tx lost after 8 years--6 years on hemodialysis (HD), clinical symptoms of severe HPTx (iPTH > 1300 pg/ml). Elective parathyroidectomy was cancelled as patient received the second graft. Then she was oliguric and required regular HD from the 4th day after Tx. We observed increasing resistance index (RI) and finally no diastolic blood flow in graft USG-Doppler scan. Ten days after Tx, the patient was revised surgically and renal biopsy was performed. No pathology but slight ATN was found. At the same time iPTH level was 1225 pg/ml. Plasmapheresis (PF) was introduced, decreasing iPTH level to 850 pg/ml, 995 pg/ml, and 345 pg/ml respectively. After the second PF urine output increased (to 600 ml). Serum creatinine level decreased from 7.3 to 1.3 mg/dL within the next 10 days. Actually (5 months post Tx) graft function remains stable (creatinine 1.2 mg/dl). The level of iPTH at the second month after Tx was 756 pg/ml, at 4th month--439 pg/ml. Case 2: M.P. 20 years old female initially on HD, then Tx, lost after 5 months because of FSGS recurrence--again HD therapy. She developed severe secondary HPTx (iPTH level > 1300 pg/ml). Planned parathyroidectomy was cancelled as she received a second transplant. After Tx she was anuric for 5 weeks and was treated with HD. She had high RI index in repeated USG-Doppler scans, blood flow in renal cortex was deceleration. Repeated renal biopsy showed no pathology and PF therapy was introduced. After the first PF the patient started to urinate, after the 5th--the urine output was 1000 ml. Overall 10 PFs were done. Now, 13 months after Tx, graft function is satisfactory (creatinine level 2.1 mg/dL). The level of iPTH in 4th month after Tx was 772 pg/ml, in 10th month--631 pg/ml. We suggest that disturbances in graft blood flow were influenced by high level of iPTH, decreased successfuly by PF therapy.

Chronic kidney disease

Protein in the urine is regarded as an independent marker for worsening of kidney function and cardiovascular disease. Hence, British guidelines append the letter "P" to the stage of chronic kidney disease if protein loss is significant. Stage 1: Slightly diminished function; kidney damage with normal or relatively high GFR (≥90 ml/min/1.73 m2) and persistent albuminuria. Kidney damage is defined as pathological abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies. Stage 2: Mild reduction in GFR (60–89 ml/min/1.73 m2) with kidney damage. Kidney damage is defined as pathological abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies. Stage 3: Moderate reduction in GFR (30–59 ml/min/1.73 m2):. British guidelines distinguish between stage 3A (GFR 45–59) and stage 3B (GFR 30–44) for purposes of screening and referral.

Contrast-induced nephropathy

Decreased kidney function European guidelines classify a pre-existing decreased kidney function to be a risk factor of contrast-induced nephropathy in the following cases: Estimated glomerular filtration rate (eGFR) < 45 ml/min/1.73 m2 of body surface area before intra-arterial administration with first-pass renal exposure (not passing lungs or peripheral circulation before kidneys), or in the intensive care unit eGFR < 30 ml/min/1.73 m2 before intravenous administration or intra-arterial administration with second-pass renal exposure Known or suspected acute kidney injury To calculate estimated GFR from creatinine, European guidelines use the CKD-EPI formula in adults ≥ 18 years, and the revised Schwartz formula in children. Swedish guidelines recommends no specific formula in children because of lack of evidence, but on the other hand recommends GFR based on cystatin C rather than creatinine in those with abnormal muscle mass or liver failure or cirrhosis.

Rare tubulopathy - primary hypophosphatemic rickets (case report).

Primary hypophosphatemic rickets is a rare disorder caused by inborn defect of renal tubular reabsorbtion and usually manifested in childhood and infancy with stunted growth and deformities of lower limbs. Patient 12 years old, female, was born to healthy parents, at 41 weeks of gestation by normal delivery and had a normal birth weight and length. She had one healthy sibling (male). Psychomotor development until the age of 2 years was normal. Since the age of 2 years deformation of legs and difficulties with walking have been observed. The Patient was consulted by Pediatric Orthopedist, Nephrologists and Endocrinologist. The blood biochemical findings revealed normal pH, normal calcium (CA), potassium (K), sodium (Na) concentrations, very low phosphate (P) with markedly elevated alkaline phosphatase (AP) and slightly elevated parathyroid hormone (PTH) concentration; urine test indicated impaired tubular function: mild glucosuria, proteinuria, and markedly increased phosphaturia. Phosphate tubular reabsorbtion (PTR) was 52%, phosphate/creatinine clearance 0,52, renal threshold phosphate concentration (TmP/GFR) 0,25 mmol/l. Genetic tests results not available yet. the diagnosis of phosphate diabetes made on the basis of clinical-laboratory data. The therapy with Inorganic phosphate (50-100mg/kg/d) and 1,25(OH)D3 40-50 ng/kg/d had been started. Childs walking abilities improved with treatment, the deformation of legs decreased, but O-legs and other skeletal deformations are still remarkable. Auxological parameters are not satisfactory. Physical growth is below the normal range (height SDS -3,78); the patient's predicted height less than target height. Biochemical monitoring performed regularly under the treatment, serum phosphate remains below normal, serum ALP is still elevated. This case is in line with other publications and indicates the difficulty to achieve normal phosphate levels and normal growth without an additional treatment with growth hormone. At this stage of the disease, the question of referring to the growth hormone therapy is being considered aimed to improve the growth tendencies. It is possible that orthopedic surgery is also needed in the future.

Contrast-induced nephropathy

Roxana Mehran score The Roxana Mehran score is a clinical prediction rule to estimate probability of nephropathy (increase ≥25% and/or ≥0.5 mg/dl in serum creatinine at 48 h): Risk Factors: Systolic blood pressure <80 mm Hg - 5 points (if systolic BP less than 80 mmHg for at least one hour requiring inotropic support) Intra-arterial balloon pump - 5 points Congestive heart failure, counting as NYHA class III (marked limitation in activity due to symptoms, even during less-than-ordinary activity) or worse, or history of pulmonary edema - 5 points Age >75 y - 4 points Hematocrit level <39% for men and <35% for women - 3 points Diabetes mellitus- 3 points Contrast media volume - 1 point for each 100 mL Decreased kidney function: Serum creatinine level >1.5 g/dL - 4 points or Estimated Glomerular filtration rate (online calculator) 2 for 40–60 mL/min/1.73 m2 4 for 20–40 mL/min/1.73 m2 6 for < 20 mL/min/1.73 m2

[Over 55 years-old live-related donor kidney transplants: a report of 12 cases].

To evaluate the risk factors of the over 55-year-old donor and the safety and efficacy of the donor, and the recipient with the immediate and long-term of the kidney. The living-related donor kidney transplantation in 15 cases was performed in our unit from October 1999 to April 2002. Of these, 12 donors were over 55 with age ranging from 55 to 73 years-old and mean age of 62, 75 years. 5 donors were male and 7 were female. Father in 5 cases and 6 and 1 were mother and grandmother, respectively. The donors were evaluated depending on general state of health, hypertension, diabate and important organa in condition; and renal function by creatinine (Cre), creatinine clearance (Ccr), Glomerular filtration rate (GFR), B ultrasound and renal arteriograph prior to operation. The all receipients with ages ranging from 14 to 46 years with end-stage renal diseases (ESRD) from and their mean age was 32.9 years. The donor' left nephrectomy was performed in 10 cases and right nephrectomy in 2. Warm-ischemia time was from 70 s to 170 s (mean time, 92 s). Cold-ischemia time was from 60 minutes to 120 minutes and mean 84 minutes. The follow-up is from 12 to 42 months and mean 20, 84 months. All the 12 donors were perfectly recovered during operation and postoperation. During their 11-day stay in the hospital no complications was observed. The donor' creatinine was raised to about 12 to 34 micro mol/L (mean, 22 micro mol/L). One recipient died from lung infection at 28 days postoperative and 1 died due to liver failure with normal graft function after transplanted 6 months and yet one recipient with delayed graft function had recovered by 12 times dialysis. The remain recipient had a better recovered. Aged (>or= 55 years-old) donor renal transplantation can be carried out as the poor supply of can be used kidney but must to controled the indication and the prepare to be accomplished seriously.

Glomerular filtration rate in examined population of Bosnian Posavina - region of Balkan Endemic Nephropathy.

Balkan endemic nephropathy (BEN) is chronic tubulointersticial nephritis of unknown aetiology characterized by an insidious onset and gradual progression to end stage renal disease (ESRD). Endemic regions of Bosnia and Herzegovina are Posavina and Semberija, sited at basin of Sava River. In BEN, just like in other chronic renal diseases (CKD), glomerular filtration rate (GFR), is assumed a marker of overall renal function. The aim of this study was to compare GFR in examinees of endemic and non-endemic region for BEN, and between examinees with and without risk factors for BEN within endemic region. Study included 603 inhabitants of Bosnian Posavina, out of whom 386 (65%) from endemic (Domaljevac) and 217 (36%) from non-endemic (Svilaj) village, and it was performed in two phases. The first phase encompassed obtaining anamnestic data (demographic, personal and family history), measurement of arterial blood pressure, and urine dipstick testing (specific gravity, pH, proteins, leukocytes, glucose, ketones, and microalbuminuria). In the second phase, besides repeated urine dipstick test, laboratory blood testing and abdominal ultrasound, with special attention to urinary tract, was also performed. We have compared GFR between examinees of endemic and non-endemic regions for BEN, and between examinees with and without family burden for BEN within endemic region, using MDRD formula for calculating GFR, with cut-off value (5th percentile) based on result of studies performed in European Caucasians in screening for CKD and for establishing stages of CKD in BEN. Medical was used for statistical testing. Out of total number of examined inhabitants (603), 145 examinees were included in the second phase. After exclusion of 17 diabetic patients, 94 (73%) examinees from endemic and 34 (27%) examinees from non-endemic region remained. In the endemic region there were 46 (49%) examinees with and 48 (51%) without family burden for BEN. Overall GFR in examined groups was within physiologic range. There was not statistically significant difference in calculated GFR between examinees of endemic and non-endemic regions for BEN (Mann-Whitney test p=0.104; Fisher's test p=1), neither between examinees with and without family burden for BEN within endemic region (Mann-Whitney test p=0,7393; Fisher's test p=0,263). Overall GFR in examined groups was within physiologic range. There wasn't statistically significant difference in calculated GFR between examinees of endemic and non-endemic regions for BEN, neither between examinees with and without family burden for BEN within endemic region. GFR, no matter how accurately calculated and estimated, does not represent significant biomarker for diagnosis, especially early diagnosis, of BEN, until maybe its overt advanced form.


Comment: The patient presents a good general condition with a recently diagnosed hepatocarcinoma, not giving him any type of treatment other than symptomatic and supportive at this stage would not be the right thing to do. TACE would not be indicated because of extrahepatic involvement. Transplantation would also not be done if he has extrahepatic disease. We are left with answers 3 and 4, both with systemic treatment (indicated because it is metastatic) and the correct answer is 4, for all the reasons given therein.

Comment: The patient presents a good general condition with a recently diagnosed hepatocarcinoma, [HIDDEN]. TACE would not be indicated because of extrahepatic involvement. Transplantation would also not be done if he has extrahepatic disease. We are left with answers 3 and 4, both with systemic treatment (indicated because it is metastatic) and [HIDDEN].

A 64-year-old man with Child A liver cirrhosis with no history of decompensation. After detection of a focal hepatic lesion on screening ultrasound, the study is completed with a thoracoabdominal CT scan. This scan showed the presence of 4 liver lesions (one of them up to 6 cm) with uptake pattern typical of hepatocarcinoma, tumor vascular invasion and a metastasis in the right adrenal gland. No ascites is observed. The patient reports only asthenia, but no general syndrome. The treatment of this patient would be:

Symptomatic and supportive treatment, since he presented an advanced hepatocarcinoma with vascular invasion and metastasis.

Transarterial chemoembolization (TACE), since the treatment increases survival in patients with advanced hepatocarcinoma.

Systemic chemotherapy with doxorubicin iv since he presents disseminated disease but he is in good general condition.

Treatment with oral sorafenib, since this is a patient with good general condition, Child A and advanced stage hepatocarcinoma BCLC-C.

The appropriate treatment is liver transplantation as it is the only procedure that completely eliminates the primary tumor and avoids future complications of cirrhosis.

Complete response for advanced liver cancer during sorafenib therapy: case report.

Hepatocellular carcinoma (HCC) is the fifth most common neoplasia in the world. In the past, treatment of advanced HCC with conventional antineoplastic drugs did not result in satisfactory outcomes: recently, in this patient population the oral multikinase inhibitor sorafenib has been able to induce a statistically significant improvement of overall survival. Similarly to other anti-angiogenic drugs employed in other tumour types, also sorafenib seldom induces the dimensional tumour shrinking usually observed with conventional cytotoxic drugs: data gathered from studies carried out with sorafenib and other competitors under development do not report any complete response in HCV-induced HCC. An 84-year old man with a long-lasting history of chronic HCV hepatitis was referred to our Institution for an ultrasonography investigation of a focal hepatic lesion. To better characterize the liver disease and clearly define the diagnosis of the focal hepatic lesion, the patient was hospitalized in our department. Laboratory and instrumental investigations confirmed the clinical picture of HCV-related liver cirrhosis and identified a hepatic lesion of about 6 cm featuring infiltrating HCC with thrombosis of the portal trunk. Due to the advanced stage of the disease, therapy with sorafenib 400 mg bid was started. Right from one month after the treatment was started, a reduction of alpha-fetoprotein level was observed which, by the third month, turned down within the normal limits. In addition the CT scan showed 50% reduction of the neoplastic lesion along with canalization of the portal trunk. At the sixth month the normalization of the alpha-fetoprotein level at the lower limit of normality was confirmed and the MRI showed complete disappearance of the neoplasia. In addition a reduction of a metallo-proteinase serum level was observed. At the twelfth month a further MRI confirmed complete response had been maintained. At present the patient is in a follow-up program to evaluate the duration of the complete response. This case is worth mentioning since, to the best of our knowledge, it represents the first evidence of complete response to sorafenib in an elderly patient with advanced HCV-related HCC.

Ultrasonography of liver tumors

Ultrasound monitoring of TACE therapy (transarterial chemoembolization) Transarterial chemoembolization (TACE) is part of palliative therapies for HCC used in intermediate stages of the disease. It consists of selective angiographic catheterization of the hepatic artery and injection of chemotherapeutic agents (usually adriamycin, but other molecules are currently the subject of clinical trials), followed by embolization of hepatic artery with gelfoam, alcohol or metal rings. A similar procedure is transarterial embolization but without chemotherapeutic agents injection, used in the treatment of hypervascular liver metastases. These therapies are based on the predominantly arterial vasculature of HCC and hypervascular metastases, while the remaining liver parenchyma has a dual vascular intake, predominantly portal. Their efficacy is high only for lesions who are hyperenhanced during arterial phase. The role of US is

Milan criteria

one lesion smaller than 5 cm; alternatively, up to three lesions, each smaller than 3 cm no extrahepatic manifestations no evidence of gross vascular invasion Under current OPTN/ONUS guidelines, patients with cirrhosis and HCC who meet these criteria may be considered for transplantation. Depending on the treatment algorithm, additional factors such as advanced liver disease (as classified by Child-Pugh score) or evidence of portal hypertension may also affect suitability for transplantation.

Ultrasonography of liver tumors

Ultrasound is useful in HCC detection, stadialization and assessing therapeutic efficacy. In terms of staging related to therapy effectiveness, the Barcelona classification is used which identifies five HCC stages. Curative therapy is indicated in early stages, which include very early stage (single nodule <2 cm), curable by surgical resection (survival 50-70% five years after surgical resection) and early stage (single nodule of 2–5 cm, or up to 3 nodules <3 cm) which can be treated by radiofrequency ablation (RFA) and liver transplantation. Intermediate stage (polinodular, without portal invasion) and advanced stage (N1, M1, with portal invasion) undergo palliative therapies (TACE and sorafenib systemic therapy) and in the end stage only symptomatic therapy applies.

Hepatocellular carcinoma

Transcatheter arterial chemoembolization (TACE) is performed for unresectable tumors or as a temporary treatment while waiting for liver transplant ("bridge to transplant"). TACE is done by injecting an antineoplastic drug (e.g. cisplatin) mixed with a radio-opaque contrast (e.g. Lipiodol) and an embolic agent (e.g. Gelfoam) into the right or left hepatic artery via the groin artery. The goal of the procedure is to restrict the tumor's vascular supply while supplying a targeted chemotherapeutic agent. TACE has been shown to increase survival and to downstage HCC in patients who exceed the Milan criteria for liver transplant. Patients who undergo the procedure are followed with CT scans and may need additional TACE procedures if the tumor persists. As of 2005, multiple trials show objective tumor responses and slowed tumor progression, but questionable survival benefit compared to supportive care; greatest benefit is seen in people with preserved liver function, absence of vascular

Adrenal metastasis from hepatocellular carcinoma (HCC): report of 3 cases.

Although autopsy reports show that the adrenal gland is the second most common organ of hematogeneous metastasis from hepatocellular carcinoma (HCC), paradoxically there is found to be a very scarce number of the adrenal metastasis in clinical practice. We have recently experienced rare patients with right adrenal metastasis from HCC. Case 1: A 51 year-old man with a 5-year history of chronic hepatitis was admitted with hematemesis to Nippon Medical School Hospital. CT revealed a main tumor associated with a few daughter tumors in the hepatic posterior segment and in addition another tumor located between the right hepatic lobe and right kidney. The diagnosis of HCC with a right adrenal gland metastasis was made, and hepatectomy and right adrenalectomy was performed. Twenty months after operation he was alive and free of disease. Case 2: A 78 year-old man underwent resection of the lateral segment of the left hepatic lobe for HCC. Twelve months later, recurrent foci in the residual liver were found and those were treated with transarterial embolization (TAE). Right adrenal metastasis was found on CT 26 months after hepatectomy. TAE was done for the hepatic recurrent tumors and adrenal metastasis. Twelve months after, he survived in good condition. Case 3: A 47 year-old man presented with liver cirrhosis with a long history. He was diagnosed as having HCC with multiple intrahepatic metastases and was treated with TAE 4 times. Follow-up CT revealed right adrenal metastasis. TAE was done for hepatic recurrent tumor and right adrenal metastasis. Three months later the patient died of liver failure.

Ultrasonography of liver tumors

The effectiveness of screening programs is proved by an increase in detection rate of HCC <2 cm (from <5% in the 90s in Europe to > 30% today in Japan) with curative therapy options. The main problem of ultrasound screening is that, in order to be cost-effective, it should be applied to the general population and not in tertiary hospitals. This raises the importance of the operator and equipment dependent part of the ultrasound examination. The efficiency of such a program is linked to the functional liver parenchyma of the cirrhotic patient. Therefore, some authors argue that screening should be excluded in patients with etiologies that prevent curative treatment or in patients with advanced liver disease (Child-Pugh class C). After curative therapies (surgical resection, local ablative therapies) continuing ultrasound screening is recommended first at 1 month then at 3 months intervals after the therapy to assess the effectiveness of therapy and to detect other nodules.

Bland embolization

The majority of patients with HCC have underlying liver disease with resultant cirrhosis. Patients with normal liver function and, presumably, normal hepatic parenchyma may undergo resection of 75% to 80% of their liver without developing postoperative hepatic failure. Patients with underlying liver disease require a greater volume of liver remnant to maintain hepatic function, thus, tumors that might normally be resectable in patients with normal liver parenchyma may not be resectable in the presence of cirrhosis. The Child-Pugh nominal liver staging system is the most accurate in predicting survival of patients with unresectable HCC treated with TACE and TAE. Patients with Child-Pugh class C cirrhosis may be more likely to die of their underlying liver disease than of their HCC and are unlikely to tolerate arterial embolization well and therefore, embolization therapy is only indicated in patients with Child A or B cirrhosis.

Hepatocellular carcinoma

Important features that guide treatment include: size spread (stage) involvement of liver vessels presence of a tumor capsule presence of extrahepatic metastases presence of daughter nodules vascularity of the tumor MRI is the best imaging method to detect the presence of a tumor capsule. The most common sites of metastasis are the lung, abdominal lymph nodes, and bone. Prevention Since hepatitis B and C are some of the main causes of hepatocellular carcinoma, prevention of infection is key to then prevent HCC. Thus, childhood vaccination against hepatitis B may reduce the risk of liver cancer in the future. In the case of patients with cirrhosis, alcohol consumption is to be avoided. Also, screening for hemochromatosis may be beneficial for some patients. Whether screening those with chronic liver disease for HCC improves outcomes is unclear.

InternalMed_Harrison

Resection Liver transplantation (CLT/LDLT) Curative treatments (30%) 5-yr survival: 40–70% Randomized controlled trials (50%) Median survival 11–20 months Symptomatic treatment (20%) Survival <3 months PEI/RF TACE Sorafenib Advanced stage (C) Portal invasion, N1, M1, PST 1-2 Intermediate stage (B) Multinodular, PST 0 Very early stage (0) Single <2 cm carcinoma in situ Single Portal pressure/ bilirubin Normal Increased Associated diseases No Yes 3 nodules ˜3 cm Stage 0 PST 0, Child-Pugh A Early stage (A) Single or 3 nodules <3 cm, PST 0 PST End stage (D) Stage D PST >2, Child-Pugh C Stage A-C PST 0–2, Child-Pugh A–B HCC

Diagnosis and treatment of hepatocellular carcinoma: An update.

Hepatocellular carcinoma (HCC) is one of the most common malignancies leading to high mortality rates in the general population; in cirrhotic patients, it is the primary cause of death. The diagnosis is usually delayed in spite of at-risk population screening recommendations, i.e., patients infected with hepatitis B or C virus. Hepatocarcinogenesis hinges on a great number of genetic and molecular abnormalities that lead to tumor angiogenesis and foster their dissemination potential. The diagnosis is mainly based on imaging studies such as computed tomography and magnetic resonance, in which lesions present a characteristic classical pattern of early arterial enhancement followed by contrast medium "washout" in late venous phase. On occasion, when imaging studies are not conclusive, biopsy of the lesion must be performed to establish the diagnosis. The Barcelona Clinic Liver Cancer staging method is the most frequently used worldwide and recommended by the international guidelines of HCC management. Currently available treatments include tumor resection, liver transplant, sorafenib and loco-regional therapies (alcoholization, radiofrequency ablation, chemoembolization). The prognosis of hepatocarcinoma is determined according to the lesion's stage and in cirrhotic patients, on residual liver function. Curative treatments, such as liver transplant, are sought in patients diagnosed in early stages; patients in more advanced stages, were not greatly benefitted by chemotherapy in terms of survival until the advent of target molecules such as sorafenib.

Metastatic liver disease

Diagnosis Hemoglobin decrease Liver function test: ALP elevated, bilirubin elevated, albumin decrease Carcinoembryonic antigen for colorectal secondaries Ultrasound scan CT scan Biopsy under ultrasound control Treatment Treatment can consist of surgery (hepatectomy), chemotherapy and/or therapies specifically aimed at the liver like radiofrequency ablation, transcatheter arterial chemoembolization, selective internal radiation therapy and irreversible electroporation. For most patients no effective treatment exists because both lobes are usually involved, making surgical resection impossible. Younger patients with metastases from colorectal cancer confined to one lobe of the liver and up to 4 in number may be treated by partial hepatectomy. In selected cases, chemotherapy may be given systemically or via hepatic artery.

InternalMed_Harrison

PEI/RFA/MWA Single lesion <5 cm Child’s A/B Tumor progression Transplant TACE/90Yttrium/ New agent trials Multifocal >5 cm Child’s A/B Sorafenib/Palliative care hormonal therapies Child’s C Bilirubin ˜2 Metastases Neoadjuvant bridge therapy RFA/TACE/90Yttrium Living donor transplant Suitable donor UNOS + criteria Ablation candidate Resection/RFA Non-cirrhotic Child’s A Single lesion No metastases Transplant candidate Transplant evaluation 1 lesion <5 cm 3 lesions all less than 3 cm Child’s A/B/C; AFP <1000 ng/mL No gross vascular invasion Not suitable for surgery Medical evaluation Comorbid factors 4 lesions Gross vascular invasion LN (+) or metastasis HCC diagnosed Cadaver donor wait list Yes Sorafenib/New agent clinical trials FIGURE 111-2 Hepatocellular carcinoma (HCC) treatment algorithm. The initial clinical evaluation is aimed at assessing the extent of the tumor and the underlying functional compromise of the liver by cirrhosis. Patients are classified as having resectable

InternalMed_Harrison

Most HCC patients have two liver diseases, cirrhosis and HCC, each of which is an independent cause of death. The presence of cirrhosis usually places constraints on resection surgery, ablative therapies, and chemotherapy. Thus patient assessment and treatment planning have to take the severity of the nonmalignant liver disease into account. The clinical management choices for HCC can be complex (Fig. 111-2, Tables 111-5 and 111-6). The natural history of HCC is highly variable. Patients presenting with advanced tumors (vascular invasion, symptoms, extrahepatic spread) have a median survival of ∼4 months, with or without treatment. Treatment results from the literature are difficult to interpret. Survival is not always a measure of the efficacy of therapy because of the adverse effects on survival of the underlying liver disease. A multidisciplinary team, including a hepatologist, interventional radiologist, surgical oncologist, resection surgeon, transplant surgeon, and medical

Milan criteria

In transplantation medicine, the Milan criteria are set of criteria applied in consideration of patients with cirrhosis and hepatocellular carcinoma (HCC) for liver transplantation with intent to cure their disease. Their significance derives from a landmark 1996 study in 48 patients by Mazzaferro et al which showed that selecting cases for transplantation according to specific strict criteria led to improved overall and disease-free survival at a four-year time point. These same criteria have since been adopted by the Organ Procurement and Transplantation Network (OPTN) in the evaluation of patients for potential transplantation.The threshold Milan criteria are as follows: one lesion smaller than 5 cm; alternatively, up to three lesions, each smaller than 3 cm no extrahepatic manifestations no evidence of gross vascular invasion

[A case of advanced hepatocellular carcinoma successfully treated by liver resection after complete response induced by sorafenib administration].

A 50-year-old man presented to our hospital with the chief complaint of right hypochondriac pain and a palpable tumor. Advanced hepatocellular carcinoma (HCC) and chronic hepatitis B infection were diagnosed and treated by twice-repeated transcatheterarterial chemoembolization (TACE) followed by administration of entecavir. Two months after the last TACE, alpha-fetoprotein(AFP)and protein induced by vitamin K absence or antagonistII (PIVKA-II) levels had elevated, and multiple small early enhancing nodules were detected on computed tomography(CT)scan. Based on his age and liver function (Child-Pugh score A5), a full dose of sorafenib (800 mg/day) was administered. The sorafenib dose was decreased after one month to 400mg/day because of hand-foot syndrome. Following sorafenib administration, the lesions shrank markedly, and complete response (CR) according to modified Response Evaluation Criteria In Solid Tumors(mRECIST)was achieved within 4 months. Six months after sorafenib treatment was begun, recurrent HCC was detected in segment 6, near the previously treated lesion. The decreased size of the main tumor and normalization of AFP levels allowed curative surgical resection. The patient was discharged 5 days after surgery and is currently treated with a half dose of sorafenib. Thirteen months after surgery, a small early enhancing lesion is visible on postoperative CT scan, but AFP and PIVKA-II levels are still keeping in a normal range. This case demonstrates that if sorafenib treatment is effective, then subsequent surgical treatment can be reconsidered in patients with advanced HCC responding to this combined therapy.

Hepatocellular carcinoma

Staging BCLC Staging System The prognosis of HCC is affected by the staging of the tumor and the liver's function due to the effects of liver cirrhosis. A number of staging classifications for HCC are available; however, due to the unique nature of the carcinoma to fully encompass all the features that affect the categorization of the HCC, a classification system should incorporate tumor size and number, presence of vascular invasion and extrahepatic spread, liver function (levels of serum bilirubin and albumin, presence of ascites, and portal hypertension) and general health status of the patient (defined by the ECOG classification and the presence of symptoms). Of all the staging classification systems available the Barcelona Clinic Liver Cancer staging classification encompasses all of the above characteristics. This staging classification can be used to select people for treatment.

Liver support system

Goals of MARS Therapy Recovery and prevention of re-transplantation • Prolong survival time and stabilize the patient to receive a re-transplant if the above goal is not achieved MARS Therapy Indication Primary graft dysfunction Hepatic encephalopathy ≥ II Increased intracranial pressure Renal dysfunction or hepatorenal syndrome. Progressive intrahepatic cholestasis Treatment Schedule: 3 to 5 eight-hour treatment sessions on consecutive days Continuous treatment with hemodynamic instability (in any case, treatment kit must be replaced every 24 hours) MARS in liver Failure after Liver Surgery Etiology: Liver Resection in hepatocellular carcinoma Transarterial Chemoembolization (TACE) Partial resection in living donor transplantation Other surgical interventions Goals of MARS Therapy Recovery until hepatic regeneration MARS Therapy Indication Hepatic encephalopathy ≥ II Renal dysfunction or hepatorenal syndrome. Progressive intrahepatic cholestasis

InternalMed_Harrison

Tumors of the Liver and Biliary Tree 552 tumor regrowth. Second, the Sorafenib HCC Assessment Randomized Protocol (SHARP) phase III trial of sorafenib versus placebo for unresectable HCC showed that survival could be significantly enhanced in the treatment arm with only 2% of the patients having tumor response but 70% of patients having disease stabilization. This observation has led to a reconsideration of the usefulness of response and the significance of disease stability. Third, HCC is a typically highly vascular tumor, and the vascularity is considered to be a measure of tumor viability. As a result, the Response Evaluation Criteria in Solid Tumors (RECIST) have been modified to mRECIST, which requires measurement of vascular/ viable tumor on the CT or MRI scan. A partial response is defined as a 30% decrease in the sum of diameters of viable (arterially enhancing) target tumors. The need for semiquantitation of tumor vascularity on scans has led to the introduction of

Bland embolization

When evaluating a patient for embolization, both the severity of the underlying liver disease and the extent of the tumor being treated should be considered. In 1999, Llovet et al, proposed the Barcelona Clinic Liver Cancer (BCLC) staging classification as a means of both classifying patients and linking their stage to a specific treatment. Although selective embolization of a solitary well circumscribed HCC in a patient with Child Class B cirrhosis might be well tolerated, embolization of a hemi-liver in a Child A patient with multifocal hepatoma involving more than 75% of the liver and with portal vein tumor thrombus may result in hepatic failure and severe death.

Sorafenib

Liver cancer At ASCO 2007, results from the SHARP trial were presented, which showed efficacy of sorafenib in hepatocellular carcinoma. The primary endpoint was median overall survival, which showed a 44% improvement in patients who received sorafenib compared to placebo (hazard ratio 0.69; 95% CI, 0.55 to 0.87; p=0.0001). Both median survival and time to progression showed 3-month improvements; however, there was no significant difference in median time to symptomatic progression (p=0.77). There was no difference in quality of life measures, possibly attributable to toxicity of sorafenib or symptoms related to underlying progression of liver disease. Of note, this trial only included patients with Child-Pugh Class A (i.e. mildest) cirrhosis. Because of this trial sorafenib obtained FDA approval for the treatment of advanced hepatocellular carcinoma in November 2007.

[Long-term survival of patients with inoperable hepatocarcinoma, treated with interventional radiology].

Survival rates in untreated patients with unresectable HCC are rather disappointing. Our study was aimed at assessing long-term survival in the patients submitted to combined transarterial chemoembolization (TACE) and percutaneous ethanol injection (PEI). We treated 223 patients, but long-term follow-up is available in 143 of them only. Eighty-seven of 143 patients had Child's A liver cirrhosis, 45 had Child's B and 6 Child's C. Five patients did not have cirrhosis. Eighty-seven patients had single lesions--45 of them < 5 cm and 42 > 5 cm. Fifty-six patients had multiple/diffuse lesions. All patients underwent TACE while PEI was performed in selected patients with single or double lesions. Survival rates were calculated with the life-table analysis by Kaplan and Meyer. Follow-up was 1-72 months (median: 28 months). At 1, 3 and 5 years, the overall survival rates were 72%, 34.5% and 16.4%, respectively. The survival rates at 1, 3 and 5 years in single lesions < 5 cm were 90.4%, 52.1% and 34.8%, respectively, vs. 69.4%, 37.4% and 18.7% in lesions > 5 cm and 58.8%, 12.5% and 0% in multiple/diffuse lesions. In conclusion, the long-term results of the radiologic treatment of unresectable HCC are comparable with surgical results obtained in selected cases.

Liver cancer

Hepatocellular carcinoma Partial surgical resection is the recommended treatment for hepatocellular carcinoma (HCC) when patients have sufficient hepatic function reserve. 5-year survival rates after resection have massively improved over the last few decades and can now ranges from 41 to 74%. However, recurrence rates after resection can exceed 70%, whether due to spread of the initial tumor or formation of new tumors . Liver transplantation can also be considered in cases of HCC where this form of treatment can be tolerated and the tumor fits specific criteria (such as the Milan criteria). In general, patients who are being considered for liver transplantation have multiple hepatic lesions, severe underlying liver dysfunction, or both.

[Successful Multimodal Treatment for Aggressive Extrahepatic Metastatic Hepatocellular Carcinoma - A Case Report].

A 38-year-old man underwent right hepatectomy for a huge hepatocellular carcinoma(HCC)in the right hepatic lobe. Four months later, recurrent and metastatic disease were observed in the remnant liver and right lung, respectively. We performed a hepatectomy for the recurrent lesion because transcatheter arterial chemoembolization (TACE) was not effective. After surgery, we initiated sorafenib treatment for the lung metastases. One year later, the lung metastases worsened and metastases were observed in the mediastinal lymph nodes, and both metastatic lesions were resected. Seven months later, para-aortic lymph nodal metastasis was observed and dissected. Three months later, metastasis to the supraclavicular lymph node was observed. We performed particle radiation therapy and a complete response was achieved. One year later, metastases in both lungs were observed and resected. Despite continued sorafenib administration throughout the clinical course, a metastasis to the left adrenal gland was observed. This lesion was extirpated because no other recurrent lesions were detected. At 4 years and 6 months after the first operation, no other recurrences have occurred. Currently, sorafenib is the initial drug of choice for HCC with extrahepatic metastases. It is possible to improve the prognosis of patients with HCC and extrahepatic metastases by applying surgical treatment during the course of sorafenib administration.

[Analysis of 293 cases of hepatocellular carcinoma of recent ten years--II. Diagnosis, therapy and prognosis].

Two hundred and ninety-three cases of hepatocellular carcinoma (HCC) of recent ten years during 1979 and 1988 were analysed on its diagnosis, therapy and prognosis. Angiography was the most useful diagnostic method for the first 5 years. During recent 5 years and for the tumor with size less than 2 cm, however, ultrasonography was the best method. 24.7% cases showed negative AFP and only 42.5% cases showed the level over 400 ng/ml. According to the tumor occupying-rate at the diagnosis, the number of cases of E1 had increased annually, the other cases being unchanged. 88.6% cases had liver cirrhosis microscopically as being reported previously. As a therapy TAE was most frequently performed, followed by operation, arterial infusion of antitumor drugs et al. The prognosis of the patients depended on the tumor occupying-rate. For the case of E1, the prognosis was the best by the therapy of ethanol injection therapy, operation and TAE. For the cases with tumor of larger than E1, frequent TAE was the best. From these results we concluded that we must make efforts to find small tumors to get the good prognosis.

[Evaluation of non-surgical treatments of hepatocellular carcinoma--investigation of the cases with long and short survivals after treatment].

One hundred and one cases of hepatocellular carcinoma (HCC) treated in Maebashi Red Cross Hospital from May 1984 to August 1987 were classified according to the therapy and progression of the disease and were investigated on their prognosis. Furthermore, "long survived group" in which, patients survived for more than one year were compared with "short survived group" in which patients died within one month after non-surgical treatment. In operated patients, the prognosis was the best, but the rate of operable cases was only 13.9%. In patients with stage IV, one year survival rate was significantly low. In patients with portal trunk invasion (Vp4), or with Child C that was the poorest functional reserve of the liver, one year survival rate was also significantly low in comparison with patients with other stages or other Child's classification. In HCC patients treated with transcatheter arterial embolization (TAE), the prognosis tended to be poor as stage and portal invasion progressed, but in regard to reserve function of the liver, the prognosis was not so poor in patients of Child C significantly as in cases of A or B. The comparisons between long and short survived group were as follows. a) In 17 cases belong to long survived group, mean survival period was 24 months and the longest one was 4 years and 10 months. On the other hand, in 10 cases belong to short survived group, mean survival period was 17 days, the shortest one was 3 days. b) The main reason of inoperability in long survived group was progression of the tumor. Complications such as diabetes mellitus, advanced age and rejection of treatment by the patient were the other reasons of in operability. In almost half of the patients in short survived group, the tumor progression and low functional reserve of liver were found in 4 patients. c) In short survived group, esophageal varices were more common and functional reserve of the liver was poorer than in long survived group. In short survived group, LDH and total bilirubin were significantly higher than those of long survived group, but there was no significant differences in transaminase value and ICG retention in 15 minutes. d) In short survived group, extent of the tumor in liver and portal invasion were advanced. Three cases of this group (30%) had distant metastasis. e) In long survived group, the main reason of death was hepatic failure. Renal failure, or pulmonary complications were also found in short survived group.(ABSTRACT TRUNCATED AT 400 WORDS)

Portopulmonary hypertension

Portopulmonary hypertension (PPH) is defined by the coexistence of portal and pulmonary hypertension. PPH is a serious complication of liver disease, present in 0.25 to 4% of all patients suffering from cirrhosis. Once an absolute contraindication to liver transplantation, it is no longer, thanks to rapid advances in the treatment of this condition. Today, PPH is comorbid in 4-6% of those referred for a liver transplant. Presentation PPH presents roughly equally in male and female cirrhotics; 71% female in an American series and 57% male in a larger French series. Typically, patients present in their fifth decade, aged 49 +/- 11 years on average. In general, PPH is diagnosed 4–7 years after the patient is diagnosed with portal hypertension and in roughly 65% of cases, the diagnosis is actually made at the time of invasive hemodynamic monitoring following anesthesia induction prior to liver transplantation.

Complete Response of Hepatocellular Carcinoma with Macroscopic Vascular Invasion and Pulmonary Metastasis to the Combination of Drug-Eluting Beads Transarterial Chemoembolization and Huaier Granule: A Case Report.

Hepatocellular carcinoma (HCC) associated with macroscopic vascular invasion and distant metastasis is an advanced-stage disease with an extremely poor prognosis and low survival rate. Therefore, there is an urgent need to develop novel therapeutic strategies to extend the lives of patients with advanced HCC. We represent a case of HCC with macroscopic vascular invasion and pulmonary metastasis responding dramatically to the combination treatment with drug-eluting beads transarterial chemoembolization (DEB-TACE) and Huaier granule. A 64-year-old man with hepatitis B virus (HBV)-induced liver cirrhosis was diagnosed with advanced HCC involved renal vein and inferior vena cava accompanied by pulmonary metastasis. The patient received three cycles of on-demand DEB-TACE from 9th September 2016 to 22nd August 2017 and combined with Huaier granule 20 g three times a day orally. Eight months following the treatment, complete response occurred with regression of HCC and vascular thrombus and disappearance of pulmonary metastasis. The levels of AFP had decreased from 8165.8ng/mL to within the normal range (1.7 ng/mL). This is the first case report of complete response of HCC to the combination treatment with DEB-TACE and Huaier granule. At the most recent follow-up, he remained in remission 36 months after cessation of treatment without clinical or imaging evidence of disease recurrence. The current overall survival is 54 months since the initial treatment. Data from this clinical case report suggest that the combination treatment with DEB-TACE and Huaier granule is a promising therapeutic option for advanced HCC with macroscopic vascular invasion and distant metastasis.

[Radiologic diagnosis of secondaries in the liver (author's transl)].

A diagnosis of secondaries in the liver carries considerable weight in prognosis and treatment, particularly pre-operatively, so that a possibly unnecessary operation may be avoided. Among techniques available for screening for metastases of the liver scintigraphy plays an important part. Besides laboratory tests and clinical examination it is relatively efficient and does not burden the patient. But they often are incapable of providing a basis for therapeutic decisions. Radiologic techniques are unsuitable (13). Knowledge and proper interpretation of indirect signs will permit guidance at the right time. In essence they serve the radiologic proof of advanced metastatic growths. Space occupying processes in the liver are the main indication for angiography. This is certainly not a routine method but makes sense when trying to identify the nature of defects shown in scintigrams (10). Where a primary tumor is known, angiography will follow scintigraphy of the liver, the search technique of choice. While the two techniques are correctly positive in 75-90% for avascular secondaries, experience of numerous investigations confirms that vascular metastases can be recognized earlier in angiograms than in scintigrams. Only angiography provides specific information differentiating metastases from a heptoma. The additional proof of primary tumors of the pancreas is important. Angiography is essential for indication and planning of partial hepatectomy. The angiographic picture does not permit conclusions from the metastases as to site and identity of the primary tumor. Critical evaluation of the radiographic techniques for early recognition of secondaries in the liver suggests humility. Only by carefully combining the various techniques will it be possible to demonstrate secondaries in the liver earlier and more frequently.

Treatment of hepatocellular carcinoma: is there an optimal strategy?

The incidence of hepatocellular carcinoma is increasing worldwide and now it accounts for as many as 1 million deaths annually, representing the third cause of cancer-related death. Surveillance programmes in the population at risk, namely cirrhotic patients, aim to detect tumours at an early stage when benefit from effective therapy may be provided. Patients with early tumours (single tumours measuring less than 5 cm or with less than 3 nodules measuring less than 3 cm in size) constitute the early stage category. These patients may be treated with surgical resection, transplantation, or percutaneous ablation, and the 5-year survival rate will exceed 50%. Patients with more advanced disease constitute the intermediate-advanced stage. Intermediate stage includes individuals without cancer-related symptoms and absence of vascular invasion and/or extrahepatic spread. They may achieve a 50% survival rate at 3 years that can be expanded by transarterial chemoembolization. Symptomatic patients with more advanced disease have a survival rate of less than 20% at 3 years. In this group of patients the efficacy of new agents should be assessed in phase II trials or randomized controlled trials versus no treatment to determine the impact of any therapy on survival. Finally, patients with end-stage disease with heavily impaired liver function (Child-Pugh class C) or severe physical impairment (performance status 3-4) die within 6 months and should receive only symptomatic treatment.

[Chemoembolization of hepatocarcinoma. Six years' experience].

This study was aimed at retrospectively assessing the effectiveness of transarterial chemoembolization by reviewing our six years' experience. From January, 1988, to December, 1993, chemoembolization was performed in more than 400 patients. Of them, 321 patients with complete follow-up were selected. The treatment was retrospectively analyzed according to survival rates. The average survival of chemoembolized patients is 12 months after the first treatment session. Average survival rates in Child A, B and C patients were, respectively, 13.79, 11.2 and 6.01 months. The patients were also divided according to tumor spread and the results follow: patients with single localizations had 15.19 months' survival, those with multiple localization 12.06 and those with tumor spread had 9.51 months' survival. The patients were divided into two groups: complete chemoembolization (group A) and incomplete chemoembolization (group B). The average survival was 15.95 months for 160 group A patients and 10.11 months for 161 group B patients. As for the number of chemoembolization sessions, 123 patients underwent only one session, 112 patients two sessions, 70 patients three, 12 patient four and 4 patients five sessions--625 sessions in all. Chemoembolization was performed every 3-4 months and was always preceded by a CT exam. Our patients were compared with an untreated group where average survival was 6.32 months. The value of CT after the first treatment in predicting survival was also studied. Finally, the methods used in all treatment are reported on, together with the general results and those in the different classes of patients.

Ultrasonography of liver tumors

Hepatocellular carcinoma (HCC) It is the most common liver malignancy. It develops secondary to cirrhosis therefore, ultrasound examination every 6 months combined with alpha fetoprotein (AFP) determination is an effective method for early detection and treatment monitoring for this type of tumor . Clinically, HCC overlaps with advanced liver cirrhosis (long evolution, repeated vascular and parenchymal decompensation, sometimes bleeding due to variceal leakage) in addition to accelerated weight loss in the recent past and lack of appetite.