Paolo Lorusso

REAPPRAISAL OF SERUM β2-MICROGLOBULIN AS MARKER OF GFR

Introduction. Beta 2 microglobulin(β2M) is filtered by the glomeruli and reabsorbed by the proximal tubularcells where it is metabolized. Its plasma concentration increases with decreasingrenal function. Aim. To compare serum creatinine(Cr) and serum β2M as markers of GFR. Patientsand Methods. In 160 adult patients, with various kidney diseasesand different GFR, serum Cr (autoanalyzer), serum β2M (RIA) and GFR (bladdercumulative method using 99mTc-DTPA as glomerulartracer) were measured in the same day. Results.A linear relationship was observed between ln GFR and both ln serum Cr (lnCr= 3.112–0.716lnGFR; r = 0.92) and ln serum β2M (lnβ2M = 4.274–0.814lnGFR; r = 0.90). With decreasing GFR the increase in serum β2M was higherthan that of serum Cr (see regression coefficients that are significantlydifferent). The normal upper limit of serum Cr corresponds to a GFR 48.1 mL/minwhile that of serum β2M to a GFR 65.0. With decreasing GFR the increaseof serum β2M occurs before than that of serum Cr. Conclusions.With declining renal function, serum β2M increases more and before thanserum Cr. Serum β2M is a good endogenous marker of GFR, better than serumCr.

99mTc-aprotinin: A new tracer for kidney morphology and function

AbstractAprotinin (Ap), a low-molecular-weight polypeptide (6500 dalton), is a protease inhibitor which is electively and stably accumulated in the kidney. In 112 adult patients, with either uni- or bilateral renal disease with different degrees of renal impairment (from normal GFR to advanced renal failure), renal scans were performed by means of Ap labelled with99mTc. Highly satisfactory renal scans were obtained in all patients. In 20 patients with renal failure (serum creatinine 1.8–8.5 mg/dl, mean 4.7) a comparison was made of the renal scans obtained with99mTc-Ap and with99mTc-DMSA.99mTc-Ap was slightly better than99mTc-DMSA, especially in patients with far advanced renal failure.Some aspects of the pharmacokinetics of99mTc-Ap were studied in 72 cases. In 22 of these patients plasma clearance of99mTc-Ap was determined by the single injection method using a two-compartment model. In patients with GFR>90 ml/min plasma clearance of99mTc-Ap was 67.6±8.4 SD ml/min. A good correlation was observed between plasma clearance of99mTc-Ap and GFR (r=0.74). After IV injection99mTc-Ap was stably fixed by the kidney. Renal radioactivity remained stable between the second and eighth hour after the injection. Urinary excretion of radioactivity measured in 35 patients in the first and in the second 2-h interval after IV injection of99mTc-Ap was negligible in all patients (2.7±1.5 SD percent of the dose in the first 2 h; 2.8±1.4 SD between the second and fourth hour). 99mTc-Ap is an excellent agent for renal imaging. It also seems promising for renal function studies.

Creatinine clearance, cystatin C, beta2-microglobulin and TATI as markers of renal function in patients with proteinuria.

BACKGROUND Proteinuria is a risk factor for end-stage renal disease (ESRD). Creatinine clearance (CrCl) is usually used as a marker to monitor the progression of ESRD, while cystatin C (CYST) has also been considered as a marker of renal function. Tumor-associated trypsin inhibitor (TATI) has been shown to be a promising marker of renal function. The aim of this study was to examine the relationship between CrCl, CYST, ß(2)-microglobulin (B2M) and TATI, with glomerular filtration rate (GFR) in patients with different levels of proteinuria. METHODS Seventy-one patients (37 males, 34 females, mean age 53 ± 15 years) were included in the study. GFR was measured by the bladder cumulative method using (99m)Tc-DTPA. Blood levels of CYST, B2M and TATI were also measured. CrCl and proteinuria were determined by 24-hour urine collection. Statistical analysis was performed with multivariate analysis. RESULTS The results are expressed as the ratio to GFR of CrCl and reciprocals of CYST (100/CYST), B2M (100/B2M) and TATI (100/TATI). The ratio CrCl/GFR increased from 1.41 in patients with proteinuria <1 g/day, to 1.66 (p<0.05) in those with proteinuria >3 g/day. The ratio 100/CYST/GFR was 1.67 and 2.28 (p<0.05), 100/B2M/GFR 0.90 and 0.69 and 100/TATI/GFR 0.14 and 0.19, respectively. Multivariate analysis demonstrated that ClCr/GFR as well as 100/CYST/GFR was independently related to the degree of proteinuria. CONCLUSIONS CrCl and CYST overestimate GFR in patients with heavy proteinuria, while the ratios 100/TATI and 100/B2M with GFR do not significantly change. The direct measurement of GFR still remains the best method to assess the progression of renal damage in patients with heavy proteinuria.

99mTc-Aprotinin for the Study of Renal Morphology and Tubular Function

The kidney has an important role in the metabolism of low-molecular weight proteins, both hormonal (insulin, glucagon, growth hormone, parathyroid hormone, calcitonin) and nonhormonal (lysozyme, β2-microglobulin interferons) (-12). Glomerular filtration and tubular reabsorption are the major renal pathways for the removal of these small proteins from the blood. Most are filtered through the glomerulus, reabsorbed at the level of the proximal tubule, and thereafter accumulated in the tubular cells where they are degraded (Figure 1). Recent evidence demonstrates that some small protein hormones, such as insulin, glucagon, growth hormone, and parathyroid hormone, also are removed from the peritubular circulation (1,3-5). A similar mechanism seems to take place also for β2 -microglobulin (11).

Low-dose synthetic adrenocorticotropic hormone-analog therapy for nephrotic patients: results from a single-center pilot study

INTRODUCTION This report describes our experience using a low-dose synthetic adrenocorticotropic hormone (ACTH) analog for patients affected by nephrotic syndrome who had not responded to or had relapsed after steroid and immunosuppressive treatments. PATIENTS AND METHODS Eighteen adult nephrotic patients with an estimated glomerular filtration rate >30 mL/min were recruited. Histological pictures included ten of membranous nephropathy, three of membranous proliferative glomerulonephritis, three of minimal change, and two of focal segmental glomerular sclerosis. All patients received the synthetic ACTH analog tetracosactide 1 mg intramuscularly once a week for 12 months. Estimated glomerular filtration rate, proteinuria, serum lipids, albumin, glucose, and potassium were determined before and during the treatment. RESULTS One of the 18 patients discontinued the treatment after 1 month because of severe fluid retention, and two patients were lost at follow-up. Complete remission occurred in six cases, while partial remission occurred in four cases (55.5% responder rate). With respect to baseline, after 12 months proteinuria had decreased from 7.24±0.92 to 2.03±0.65 g/day (P<0.0001), and serum albumin had increased from 2.89±0.14 to 3.66±0.18 g/dL (P<0.0001). Total and low-density lipoprotein cholesterol had decreased from 255±17 to 193±10 mg/dL (P=0.01), and from 168±18 to 114±7 mg/dL (P=0.03), respectively. No cases of severe worsening of renal function, hyperglycemia, or hypokalemia were observed, and no admissions for cardiovascular or infectious events were recorded. CONCLUSION Tetracosactide administration at the dosage of 1 mg intramuscularly per week for 12 months seems to be an acceptable alternative for nephrotic patients unresponsive or relapsing after steroid-immunosuppressive regimens. Further studies should be planned to assess the effect of this low-dose ACTH regimen also in nephrotic patients not eligible for kidney biopsy or immunosuppressive protocols.

A reappraisal of the bladder cumulative method as a reliable technique for the measurement of glomerular filtration rate.

In order to quantify the decline in renal function, repeated measurements of GFR are necessary. The conventional procedure is cumbersome and time expending so that alternative clearance techniques are needed. We propose a simple isotopic technique for measuring GFR by 99mTc-DTPA and external counting of the bladder by gamma camera (bladder cumulative method). This consists in the measurement by external counting of the amount of labelled filtration marker accumulated in the bladder after intravenous bolus injection. In 36 adult patients with all degrees of renal impairment (serum creatinine 0.9-9.3 mg/dL) GFR was measured twice, once by the conventional method (continuous i.v. infusion of the filtration marker and urine collection by spontaneous voiding) and once by the bladder cumulative method. 99mTc DTPA was used in performing both methods. A satisfactory agreement was found between GFR measured by bladder cumulative method (BCM) and by conventional method (CM). The BCM averaged 60.0 +/- 36.7 mL/min and the CM +/- SD averaged 62.8 +/- 36.6 mL/mm. The ratio BCM/CM +/- SD was 0.95 +/- 0.14 (y = 0.94x + 1.14; r = 0.94). Considering the 17 patients with renal insufficiency (GFR < 60 mL/min) an even better agreement between the two methods was found. In these patients the BCM averaged 28.4 +/- 17.2 mL/min; the CM averaged 29.1 +/- 16.6 mL/min; and the ratio BCM/CM was 0.96 +/- 0.08 (y = 1.03x - 1.47; r = 0.99). The day-to-day variability of BCM, studied in another 11 patients, was lower than that of creatinine clearance (variation coefficient for duplicate measurements: 7.18 +/- 6.65 SD for BCM, 15.68 +/- 8.80 SD for CM, p < 0.01). The bladder cumulative method is a simple procedure for the accurate measurement of GFR, in particular in patients with renal insufficiency. It represents a reliable tool for estimating the decline in renal function.

Long-term ACTH low-dose in a case of membranous nephropathy

The anti-proteinuric effect of a synthetic ACTH-analog, Tetracosactide, has been reported in membranous nephropathy resistant to previous treatments with steroids and immunosuppressive agents, as well as in other glomerulonephritis. ACTH-analog induced changes on melanocortin receptors of podocytes are the main antiproteinuric mechanisms of action. Unfortunately, recurrences of nephrotic syndrome are quite common after ACTH-analog discontinuation. We report a case of a 20 years old female patient affected by membranous nephropathy, with nephrotic syndrome and normal renal function, which resulted resistant to steroids and cyclosporine therapy. Then she was treated by Tetracosactide (1 mg i.m. per week, for 12 months): after 6 months complete remission occurred, but a relapse was observed 6 months after the discontinuation of the therapy. A second cycle with Tetracosactide was repeated with a new complete remission after 10 months of therapy. After the one-year treatment period, ACTH-analog was continued using a maintenance dose of 1 mg i.m. once a month: up to now, after 24 months of once-a-month Tetracosactide administration, no relapse, no side effect and no detrimental effect on renal function have been observed. This case suggests that a very low-dose and long-term Tetracosactide administration may be an effective and well tolerated therapeutic chance in patients with nephrotic syndrome resistant to steroid and/or immunosuppressive agents to avoid relapses.

UNINEPHRECTOMY INCREASES KIDNEY β2-MICROGLOBULIN: CAN IT PLAY A ROLE IN THE PROGRESSION OF KIDNEY DAMAGE?

β2-microglobulin (β2M) is highly accumulated by the kidneys of normal rats. The aim of this study was to verify if uninephrectomy can modify the renal uptake of labeled β2M. For this purpose the radioactivity of plasma and those of the remaining kidney, liver and urine have been measured in uninephrectomized rats (NX) and in controls (C) at different times after the injection as i.v. bolus of 131I-β2M. The experiments were performed in 114 Sprague-Dawley male rats. Fifty seven animals underwent right nephrectomy, the other animals being the C. NX and their C were divided in 3 groups, studied 2, 4 and 6 weeks after nephrectomy, respectively. Part of the animals were sacrificed 12 min after the injection of labeled β2M (peak-time, i.e. time of highest kidney accumulation of 131I-β2M in the normal rat) and part 10 min later. The results demonstrate that: uninephrectomy increases plasma retention of 131I-β2M kidney uptake (total and per gram) is always higher in NX liver uptake (much lower than that of kidney) is not influenced by uninephrectomy urine excretion of radioactivity is minimal in both NX and C.The behavior of β2M is similar to that we previously observed with α1-microglobulin and lysozyme. The higher kidney content of some low mw proteins after uninephrectomy could play a role in the progressive reduction of renal function determined by the reduction of renal mass.

Indapamide: Antihypertensive Activity and Renal Effects

Indapamide is a sulphonamide derivative with definite antihypertensive activity. The aim of this study is the evaluation of the antihypertensive efficacy and the effect on renal function of Indapamide in hypertensive patients with different degrees of renal function.