A 41-year-old male was referred to our Nephrology Unit because of worsening of kidney function and proteinuria. He was born at term of a normal pregnancy from apparently healthy, nonconsanguineous parents. The patient's early development was normal and he had no evident clinical problem until 18 years of age, when he developed seizures triggered by light and recurrent headaches. He was prescribed Valproic Acid and started a discontinuous follow-up in Neurology. In 1991 (age 22) EEG revealed well-represented alpha background activity, with a complex wave-peak after 7-10 flashes/sec, an expression of an epileptogenic photosensitive centroencephalic focus. In 1992, in the presence of signs of myopathy (asthenia, increase of serum lactate, myalgia), a muscle biopsy showed non-specific changes (occasional small red sub-sarcolemmal deposits, showing oxidative enzymatic activity). In 1992 the patient's sister (3 years younger) developed generalized seizures and myopathy. Genetic counseling suggested the presence of a mitochondrial disease.
Detection of the 3243A > G mutation of mitochondrial DNA confirmed the diagnosis of MELAS syndrome in the patient, his sister, his mother and one of the mother's sisters.
In the subsequent decade, he started and discontinued different types of anticonvulsant therapy (including Lamotrigine and Phenobarbital), and developed recurrent seizures, with imaging evidence of an ischemic lesion in the left hemisphere, progressive bilateral sensorineural hearing loss and sensitive distal polyneuropathy with increasing muscle weakness. On various occasions, lactic acidosis was found (lactic acid 10-13.5 mmol/L; normal <2 mmol/L).
In July 2009 (age 39) he was diagnosed with diabetes mellitus (weight loss, polyuria and polydipsia); at diagnosis, glycated hemoglobin was 19.6% and glycemia <500 mg/dL. Insulin treatment was started. Soon after diagnosis, he developed a sepsis due to Klebsiella pneumoniae. A CT scan, performed on the suspicion of a pyelonephritis focus, showed a solid hypervascularized mass, highly suggestive of neoplasia, in the right kidney. During hospitalization, serum creatinine was 0.9 mg/dL; 24-hour proteinuria was absent at repeated urinalysis; glomerular filtration rate (eGFR) was 62 mL/min (Cockcroft and Gault formula). He was normotensive (usual blood pressure 120/80 mmHg) and remained so during follow-up.
In November 2009 the patient underwent right nephrectomy. At surgery, a second small superficial tumor was detected. The histological examination identified a renal oncocytoma (2 cm); a smaller lesion (0.5 cm) had an appearance highly suggestive of chromophobe carcinoma. However, the lesion could also represent a tumoral focus of tubular oncocytosis and a precursor of another oncocytoma (Figures and ). The cytogenetic analysis was not performed, in this case; however, the two lesions are highly correlated, and a further definition was considered as of minor clinical relevance.
At hospital discharge, serum creatinine was 1.17 mg/dL with mild proteinuria (30 mg/dL). In the same year the patient's sister developed breast cancer and was identified as a carrier of the BRCA-2 mutation. However, the other family members, including our patient, preferred not to perform genetic testing for the BRCA mutation.
In January 2011 the patient was referred to our center. Glycemic control was good (glycated hemoglobin 6.5% on Repaglinide). Blood pressure was normal, without therapy. Cognitive impairment and psychomotor agitation, choreiform movements and intentional tremor, nystagmus and lower limb muscle weakness, hypotrophy and severe muscle wasting were present (height 155 cm, weight 36 Kg, BMI: 15). His speech was slow, slurred but coherent, and he appeared severely depressed. His last biochemical tests were: serum creatinine 2.1 mg/dL (eGFR 23 mL/min), proteinuria 3.6 g/24 hours, low-normal total proteins (6.2 g/dL) and normal serum albumin (3.7 g/dL). EKG was normal; no sign of cardiomyopathy was detected. Further tests showed: low IgG levels (499 mg/dL), normal IgA and IgM (213 and 115 mg/dL respectively); high PTH (445 pg/mL); moderate acidosis (pH 7.227; HCO3 22.8; SBE -3.7; normal lactates: 1.2 mmol/L); antinuclear antibodies and ANCA were negative.
Renal ultrasounds showed moderate medullary hyperechogeneity, consistent with tubulo-interstitial or vascular damage.
The rapid progression of kidney disease, with the development of nephrotic proteinuria, led us to review the samples of kidney tissue at a distance from the cancer lesions.
Of note, the changes were recorded before the onset of proteinuria and in the absence of hypertension, both at nephrectomy and over the follow-up.
Morphological examination revealed a widespread interstitial fibrosis and marked vascular changes characterized by intimal fibrosis of arcuate and interlobular arteries with a wedge-shaped area of interstitial fibrosis and tubular atrophy extending to the renal capsule suggestive of ischemic damage (Figure ). Hyaline arteriolosclerosis (Figures and ) and signs of chronic inflammation were also seen. These severe vascular lesions were the basis of the different glomerular alterations including ischemic and obsolescent glomeruli. The obsolescent glomeruli amounted to approximately 50% of the more than 100 glomeruli sampled. Some rare glomeruli (about 5-10%) showed focal segmental glomerulosclerosis, which in this context can be interpreted as consequent to the vascular alterations.
As the patient subsequently developed nephrotic syndrome, these lesions suggest that silent ischemic changes may result in the development of focal segmental glomerulosclerosis secondary to nephron loss, at least in some cases of MELAS-related nephropathy.
The formula for computing Cockcroft-Gault is given by CrCl = ((140 - age) * adjusted weight * (gender_coefficient)) / (serum creatinine * 72), where the gender_coefficient is 1 if male, and 0.85 if female. The serum creatinine concentration is in mg/dL.
The patient's gender is male, which means that the gender coefficient is 1.
The patient is 41 years old. 
The concentration of creatinine is 2.1 mg/dL. 
The formula for computing the patient's BMI is (weight)/(height * height), where weight is the patient's weight in kg and height is the patient's height in m.
The patient's height is 155.0 cm, which is 155.0 cm * 1 m / 100 cm = 1.55 m. The patient's weight is 36.0 kg. The patient's bmi is therefore 36.0 kg / (1.55 m * 1.55 m) = 14.984 kg/m^2.The patient's BMI is 15.0, indicating they are underweight.
Because the patient is underweight, we take the patient's weight, 36.0 kg as the patient's adjusted weight needed for the Cockroft-Gault Equation. 
Using the Cockcroft-Gault equation:
CrCl = ((140 - age) * adjusted weight * gender_coefficient) / (serum creatinine * 72).
Plugging the patient's values gives us ((140 - 41) * 36.0 * 1) / (2.1 * 72) = 23.571 mL/min. Hence, the patient's creatinine clearance is 23.571 mL/min.