Are prediction equations for glomerular filtration rate useful for the long-term monitoring of type 2 diabetic patients?

Background. The aim of this study was to compare the accuracyof prediction equations [modification of diet in renal disease(MDRD), simplified MDRD, Cockcroft–Gault (CG), reciprocalof creatinine and creatinine clearance] in a cohort of patientswith type 2 diabetes. Methods. A total of 525 glomerular filtration rates (GFRs) using¹²⁵I-iothalamate were carried out over 10 years in 87 type 2diabetic patients. Accuracy was evaluated at three levels ofrenal function according to the baseline values obtained withthe isotopic method: hyperfiltration (GFR: >140 ml/min/1.73m²; 140 isotopic determinations in 27 patients), normal renalfunction (GFR: 140–90 ml/min/1.73 m²; 294 isotopic determinationsin 47 patients) and chronic kidney disease (CKD) stages 2–3(GFR: 30–89 ml/min/1.73 m²; 87 isotopic determinationsin 13 patients). The annual slope for GFR (change in GFR expressedas ml/min/year) was considered to ascertain the variabilityin the equations compared with the isotopic method during follow-up.Student's t-test was used to determine the existence of significantdifferences between prediction equations and the isotopic method(P < 0.05 with Bonferroni adjusted for five contrast tests). Results. In the subgroup of patients with hyperfiltration, aGFR slope calculated with ¹²⁵I-iothalamate –4.8 ±4.7 ml/min/year was obtained. GFR slope in patients with normalrenal function was –3.0 ± 2.3 ml/min/year. In bothsituations, all equations presented a significant underestimationcompared with the isotopic GFR (P < 0.01; P < 0.05). Inthe subgroup of CKD stages 2–3, the slope for GFR with¹²⁵I-iothalamate was –1.4 ± 1.8 ml/min/year. Thebest prediction equation compared with the isotopic method provedto be MDRD with a slope for GFR of –1.4 ± 1.3 ml/min/year(P: NS) compared with the CG formula –1.0 ± 0.9ml/min/year (P: NS). Creatinine clearance presented the greatestvariability in estimation (P < 0.001). Conclusions. In the normal renal function and hyperfiltrationgroups, none of the prediction equations demonstrated acceptableaccuracy owing to excessive underestimation of renal function.In CKD stages 2–3, with mean serum creatinine 133 µmol/l(1.5 mg/dl), the MDRD equation can be used to estimate GFR duringthe monitoring and follow-up of patients with type 2 diabetesreceiving insulin, anti-diabetic drugs or both.     

Vitamin D3 Metabolites in Chronic Renal Failure and After Renal Transplantation

Circulating vitamin D3 metabolites were measured in 31 adultpatients with chronic renal failure and 31 adults between 3and 30 months after renal transplantation. No subject excretedover 1 g urinary protein daily nor received vitamin D or itsmetabolites. There was a positive correlation between 1,25(OH)₂D3and GFR between 15 and 90 ml/min in both chronic renal failure(r=0.60, P<0.001) and transplant subjects (r=0.49, P<0.01)and between 1.25(OH)₂ and 25(OH)D3 after transplant (r=0.69,P<0.001), but not in chronic renal failure (r=0.22, P=ns).There was a weak inverse correlation between 1,25(OH)₂D3 andserum phosphate in chronic renal failure (r=0.36, P<0.05)but not post transplant (r=0.03, P=ns). Compared with 1,25(OH)₂D3concentrations in 16 normal subjects (mean±SEM: 39.5±1.9 pg/ml), chronic renal failure subjects with mild renal impairment(GFR 45–90 ml/min, mean: 61.5±3.3 ml/min, n=17)had reduced 1,25(OH)₂D3 (28.9±2.7 pg/ml, P<0.01).In transplant subjects with mild impairment (GFR 45–90ml/min, mean: 61.4±3.7), 1,25(OH)₂D3 was positively (r=0.79,P<0.001) and iPTH inversely correlated (r=0.51, P<0.05)with 25(OH)D3. In each of nine such subjects studied, seasonalvariations in 1,25(OH)₂ (P<0.001) and PTH (P<0.05, 1-tailedtest), as well as in 25(OH)D3 and 24,25(OH)₂D3 were observed.We conclude that (1) 1,25(OH)₂D3 may be reduced early in thecourse of chronic renal failure and that (2) because of abnormaldependence of 1 ,25(OH)₂D3 on 25(OH)D3, low 25(OH)D3 may resultin reduced 1,25(OH)₂D3 values post transplant. Increased PTHin such cases suggests the functional significance of theseobservations.     

Time course of inulin and creatinine clearance in the interval between two haemodialysis treatments

BACKGROUND: Urinary volume of haemodialysis patients with residual renalfunction increases during the interdialytic interval. The contributionof GFR to this change in water and solute excretion has notbeen quantified in detail. The creatinine clearance (Cl^c) asa determinant of the GFR may overestimate GFR caused by thetubular secretion of creatinine. Cimetidine has been used toinhibit the secretion of creatinine in non-dialysed patients.No data are available on its usefulness in haemodialysis patients. METHODS: Two identical interdialytic intervals (DI) of 3 days (DI-1,DI-2) were investigated in 11 patients. The interval betweenDI-1 and DI-2 was 1 week. During DI-2 cimetidine 800 mg dailywas administered. Each DI was divided in four urine-collectionperiods. RESULTS: The water and solute excretion in DI-1 and DI-2 were similar.Urinary production increased from 0.37 ±0.30 ml/min to0.66 ±0.33 ml/min (P<0.05), inulin clearance (C1¹)increased from 1.8±1.1 ml/min to 2.7 ± 1.2 ml/min(P<0.05), fractional sodium excretion from 9.0 ± 5.7%to 14.5 ± 9.0% (P<0.05). In contrast to Cl_i;; theCl_c showed no increase during the interdialytic interval bothin DI-1 and DI-2. The overestimation of GFR by creatinine (Cl_i– Clⁱ) decreased during DI-1 from 1.35 ±1.69 ml/minto 0.26 ± 0.60 (P<0.05) and during DI-2 from 1.01±1.33 ml/min to 0.10 ± 0.67 (P<0.01). The ratioCl^c/Clⁱ decreased during DI-1 from 1.78 ± 0.53 to 1.09± 0.19 (P< 0.01) and during DI-2 from 2.02 ±1.13to 1.05 ± 0.30 (P<0.01). All parameters were not differentbetween the comparable days of DI-1 and DI-2. CONCLUSION: We conclude that the urinary volume in the interdialytic intervalis directly related to changes in GFR. During the interdialyticinterval GFR increased and tubular secretion of creatinine decreased.The administration of cimetidine did not improve the accuracyof Cl_c as a measurement of GFR in end-stage renal failure.     

Constant infusion clearance is an inappropriate method for accurate assessment of an impaired glomerular filtration rate

Recently renewed interest has been focused on constant infusionclearance to assess GFR accurately. In this study we comparedGFR and ERPF calculated from the constant infusion method (CIM= I x V/P) with that calculated from the standard method (StM= UxV/P), in 100 patients with renal disease who were subdividedin four groups according to their GFR-StM (<30;30–60;60–90; >90 ml/min). After a priming dose, a constantinfusion of ¹²⁵I-iothalamate (=GFR) and ¹³¹I-hippurate (=ERPF)was started at 9 a.m. The infusion rates were individually adjustedto the GFR which was approximated from the serum creatinineconcentration. After a 90-min equilibration period, GFR-StMand ERPF-StM were determined for two 2-h periods. These valueswere compared with GFR-CIM and ERPF-CIM calculated from theplasma concentration of the respective tracers at the end ofeach 2-h period (=210 and 330 min). In the patient group with GFR-StM <30 ml/min, the ¹²⁵I-iothalamateplasma concentration increased progressively over time. Consequently,average GFR-CIM at 210 min (34.2, SE±2.1 ml/min) washigher than the GFR-CIM at 330 min (31.9, SE±2.0 ml/min;P<0.001). In addition both values were significantly higherthan the corresponding GFR-StM values (18.1±2.4 and 15.3± 1.6 ml/min respectively). In the two patient groupswith GFR-StM > 60 ml/min, the ¹²⁵I-iothalamate plasma concentrationdecreased progressively over time. Consequently in both groupsGFR-CIM at 210 min was significantly lower than GFR-CIM at 330min. In all groups the ¹³¹I-hippurate plasma concentrationswere constant during the second 2-h period. Because constantplasma concentrations of ¹²⁵I-iothalamate are not obtained duringa 330 min period and GFR-CIM overestimates GFR-StM in patientswith low GFRs, we conclude that the constant infusion techniqueis not a valid method to assess GFR accurately if renal functionis impaired.     

Age as a determinant of glomerular filtration rate in non-insulin-dependent diabetes mellitus

BACKGROUND: The level of glomerular filtration rate (GFR) and its determinantsin non-insulin-dependent diabetes mellitus (NIDDM) are currentlycontroversial. DESIGN OF THE STUDY: We measured GFR and effective renal plasma flow (ERPF) in 121consecutive NIDDM without evidence of overt diabetic nephropathy.Age varied from 28 to 70 years, 61.2% were women and known durationof NIDDM was 0–37 years. Hypertension was detected in36.4% of patients and 47.8% had microalbuminuria. RESULTS: An inverse correlation was found between GFR and age, but notwith known duration of NIDDM. It was a weak correlation (r=–0.41)but statistically significant (P<0.001). The other variablesconsidered were not significant by multiple stepwise regressionanalysis, but patients with lower GFR tended to have diabeticretinopathy more frequently. GFR was lower in hypertensive comparedto normo tensive patients (123±28.4 versus 136±32.5ml/min/1.73 m²; P<0.05), but was not different between patientswith normal and elevated albumin excretion rate. ERPF also hadan inverse correlation with age (r=–0.45, P<0.001). CONCLUSION: We conclude that (i) age should be considered as a confoundingvariable when evaluating GFR in patients with NIDDM, and (ii)the age-dependent decline in GFR may mask hyperfiltration inthe early stages of diabetic nephropathy in NIDDM.     

Correlation between glomerular morphology and renal haemodynamic response to amino-acid administration in patients with IgA nephropathy

RATIONALE.: To establish relationship, if any, between renal morphologyand renal haemodynamic response to amino acids. DESIGN AND METHODS.: We investigated the correlation between renal haemodynamic regulationand morphology in a group of 15 patients with primary IgA nephropathy(IgAN) (age 26±2 years, BMI 24.4±1, GFR 64±5ml/min, RPF 377±34 mI/mm, FF 0.17±0.02). Twelvenormal subjects (age 30±3 years, BMI 24±1, GFR82±6 ml/min, RPF421±42 ml/min, FF 0.19±0.02)were studied as controls. IgA patients were divided into twogroups according to the histological staging of glomerular lesions:group I (n=7) stage II, and group II (n=8) stage III–IV. RESULTS.: In the basal state GFR was similar in the two groups and averaged64±9 and 64±6 ml/mm respectively. In contrast,FF was significantly lower in group II(0.14±0.01) (P<0.05)in comparison to group I (0.21±0.03) and controls (0.19±0.02).In order to evaluate the renal functional reserve, all studygroups underwent to an intravenous amino-acid infusion designedto increase plasma amino acid levels twofold (total from 2096±145to 4301±221 µmol/l in IgA nephropathy patientsand from 2272±83 to 3844±238 µmol/l in controls).In response to amino-acid infusion, GFR rose significantly ingroup I (GFR 20±2% and RPF 37±4% versus basal)and controls (GFR 20±2% and RPF 20±3% versus basal)(both P<0.01 vs basal). In contrast, in patients with moresevere glomerular lesions (group II) neither GFR nor RPF rosesignificantly (GFR –1±4% and RPF –8±6%versus basal) (P NS versus basal, P<0.01 versus group I andcontrols). CONCLUSIONS.: The data show that in IgA nephropathy: severe forms of glomerularlesions are associated with a complex alteration of glomerularhaemodynamic regulation, characterized by lower basal FF andloss of haemodynamic response to hyperaminoacidaemia.     

A double-blind, randomized, placebo-controlled study of nifedipine on early renal allograft function

A double-blind, randomized, placebocontrolled study was conductedto determine the effect of nifedipine on early renal allograftfunction when added to a triple therapy immunosuppression regimecomprising low-dose cyclosporin (CsA), prednisolone and azathioprine.Fifty adult cadaveric renal allograft recipients were randomizedto placebo (group P n=17), nifedipine 10 mg preoperatively and20 mg b.d. postoperatively for 48 h, followed by matching placebofor 3 months (group NS n=16) or nifedipine 10 mg preoperativelyand 20 mg b.d. postoperatively for 3 months (group NL n=17).Donor and recipient exclusion criteria included recent calciumantagonist treatment. At 3 months after transplantation meanGFR adjusted for graft loss was significantly higher in groupNL than in NS (mean ± SD 61±28 versus 34 ±25 ml/min/1.73 m²; P<0.05), group P being intermediate (45± 34ml/min/1.73 m²). Similarly, effective renal bloodflow (ERBF) at 3 months was higher ingroup NL than in groupsP and NS (mean ± SD 351 ± 175 versus 216±166and 220±162 ml/min/ 1.73 m²; P<0.05). The differenceswere not significant by 6 months post-transplantation. Thisstudy suggests that oral nifedipine commenced preoperativelyand continued for 3 months following transplantation has beneficialeffects on early renal allograft function whenincorporated aspart of an immunotherapy regimen based on cyclosporin.     

Hyperuricaemia in cyclosporin-treated patients: a GFR-related effect

BACKGROUND: Hyperuricaemia is a well known side-effect of cyclosporin A(CsA) treatment. The pathogenic mechanisms, however, remaincontroversial. There is no convincing evidence that hyperuricaemiais due to CsA-induced, impaired tubular handling of uric acid.The impact of diminished GFR in this particular context hasnever been investigated. METHODS: We prospectively studied plasma uric acid, inulin clearances,and fractional clearances of uric acid in two groups of CsA-treatedpatients (bone-marrow transplant patients, n=50; renal transplantpatients, n=32), and one healthy control group without CsA (livingrelated kidney donors, n=28). Bone-marrow transplant patientswere examined before transplantation and 6, 12, 18, 24 monthsafter transplantation, renal transplant patients 1 year aftertransplantation, and living related kidney donors before and1 year after unilateral nephrectomy. RESULTS: After 1 year of CsA treatment, hyperuricaemia was found in 36%of bone-marrow transplant patients and in 53% of renal transplantpatients. Thirty per cent of living related kidney donors wereborderline hyperuricaemic 1 year after unilateral nephrectomy.The fractional clearance of uric acid, measured serially inbone-marrow transplant patients did not change significantlyover time; it was, however, slightly higher during CsA treatmentthan after CsA withdrawal. Moreover, the bone-marrow transplantpatients' fractional clearance of uric acid was not statisticallydifferent from the renal transplant patients' and the livingrelated kidney donors' (values 1 year after transplantation/unilateralnephrectomy: bone-marrow transplant patients, 15.3±2.3%;renal transplant patients, 11.9±0.9%; living relatedkidney donors, 11.1±0.8%). The GFR at 1 year, measuredby inulin clearance, was identical in the CsA-treated groupsand slightly higher in the living related kidney donors (bone-marrowtransplant patients, 51±6 ml/min per 1.73 m² renal transplantpatients, 49±3 ml/min per 1.73 m² living related kidneydonors, 61±2 ml/min per 1.73 min²). CONCLUSIONS: There is no evidence for impaired tubular handling of uric acid,induced by a CsA-specific tubulotoxic effect. Hyperuricaemiain CsA-treated transplant patients can therefore be attributedto the cyclosporin associated decrease of GFR.     

Longitudinal analysis of performance of estimated glomerular filtration rate as renal function declines in chronic kidney disease

Background. Numerous studies have assessed the accuracy of equationsestimating glomerular filtration rate (eGFR) from serum creatininein individuals with chronic kidney disease (CKD) in cross-sectionalstudies. Limited literature exists, however, on the consistencyof performance of these equations in longitudinal studies asrenal function declines. Methods. Radionucleotide-measured GFR from 155 predialysis patientswith stage 3–5 CKD was compared with eGFR derived fromfour equations [6-variable Modification of Diet in Renal Disease(6-MDRD), 4-variable MDRD (4-MDRD), Cockcroft–Gault (CG)and Cockcroft–Gault equations corrected for body surfacearea (CGC)] at baseline, 12 and 24 months. Bias (differencebetween eGFR and measured GFR) was used as a measure of performance.Restricted Maximum Likelihood (REML) models were used to identifyvariables potentially affecting the performance of estimatingequations across time. Results. Mean measured GFR (±SD) at baseline, 12 and24 months was 25.9 ± 10.7, 23.1 ± 10.6 and 20.3± 10.1 mL/min/1.73 m², respectively. There was a statisticallysignificant negative association between bias and GFR for allfour estimates (range: –0.76 to –0.71, P < 0.001for all), indicating worsening underestimation and overestimationat higher and lower GFR, respectively. This negative associationsignificantly reduced over the 24 months (P < 0.001); however,this was largely due to persistent underestimation of eGFR fromindividuals with GFR >50 mL/min/1.73 m². For those with abaseline GFR <50 mL/min/1.73 m², the change in bias for anyof the four equations over 24 months was 1.1 mL/min/1.73 m²,suggesting relatively preserved performance with time. The MDRDequations showed a sustained advantage in estimating renal functionthat was more evident as GFR declined. Conclusion. GFR estimates are inexpensive and show an acceptablelongitudinal performance for monitoring CKD patients with GFR<50 mL/min/1.73 m². Inaccuracies appear more substantialabove this level of GFR, and care with interpretation is required.     

Renal effects of maintenance low-dose cyclosporin A treatment in psoriasis

The renal effects of low-dose cyclosporin A (CsA) treatmentin severe psoriasis was investigated in 10 patients treatedwith a mean CsA dose of 3.23 (range 1.94–4.10) mg/kg/dayfor 12 months. The psoriasis area and severity index was reducedby 63–76%. Ambulatory GFR (iothalamate-¹²⁵I) ERPF (hippuran-¹³¹),RVR and MAP were examined at 3-months intervals. A control renalbiopsy was performed shortly before treatment start and a secondbiopsy was taken after 12 months of therapy. GFR was slightlybut significantly reduced after 6 and 9 months; after 12 monthsthe decrease was not significant (121.0±7.6 versus 115.2±7.8ml/min/l.73M P>0.10). After 12 months serum creatinine increasedfrom 82±4 to 94±7 µmol/litre (P<0.05while an insignificant increase of ERPF was seen and FF decreasedfrom 0.29±0.01 to 0.26±0.01 (P<0.05). MAP remainedunchanged. GFR and serum creatinine correlated significantlywithin each 3-month interval. A slight de novo interstitialfibrosis was seen in the second biopsy in 4 of 10 patients receivinga mean CsA dose of 3.2–4.1 mg/kg/day. In three of thesepatients a concomitant rise in serum creatinine was seen. In conclusion, low-dose CsA was associated with reversible fallin GFR and potentially progressive structural changes not alwaysaccompanied by corresponding functional alterations. One shouldconsider reducing the daily dose of CsA to 3.0 mg/kg body- weightor less in CsA therapy up to 1 year.     

Contrasting Effects of Acute Angiotensin Converting Enzyme Inhibitors and Calcium Antagonists in Transplant Renal Artery Stenosis

Deterioration of renal function is a major concern during treatmentby converting enzyme inhibitors of hypertensive kidney recipientswith transplant renal artery stenosis. However, there has beenno assessment of the frequency of this complication and itsspecificity for converting enzyme inhibitors as compared toother antihypertensive drugs. The effect of acute administrationof captopril on mean arterial pressure, glomerular filtrationrate (GFR) (creatinine clearance) and effective renal plasmaflow (clearance of ¹³¹I-hippuran) was assessed in eight hypertensivepatients with transplant renal artery stenosis. Captopril induceda decrease in mean arterial pressure (128±6–121±7mmHg) and a reduction in GFR (59±8–44±8ml/minper 1.73m², P<0.05). The decrease in GFR was observed inseven out of eight patients and varied between 0% and 100% ofthe pre-captopril value. Effective renal plasma flow was maintained(157±47–141 ±24m1/min per 1.73m²) and filtrationfraction decreased by 15±7%. The effect of captoprilwas compared to that of nifedipine (N=20 mg) in four patients.Despite a larger decrease in mean arterial pressure (130±7–109±10mmHg), no reduction in GFR was observed (68±13–71.4±8).Effective renal plasma flow was unchanged and filtration functionslightly increased. Surgical or percutaneous transluminal angioplastyin five patients suppressed the captopril-induced decrease inGFR. We conclude that (1) renal insufficiency induced by convertingenzyme inhibitors is frequent in severe transplant artery stenosis;(2) renal function is well maintained during nifedipine-inducedreduction in blood pressure; (3) renal insufficiency inducedby converting enzyme inhibitors is not due to reduction of systemicblood pressure but to intrarenal effects of angiotensin II.     

Progression rate to end-stage renal failure in non-diabetic kidney diseases: a multivariate analysis of determinant factors

BACKGROUND.: The respective contribution of the type of nephropathy, gender,and proteinuria, and of the potentially alterable factors bloodpressure level and daily protein intake on the rate of progressionin non-diabetic renal diseases is debated. METHODS.: We retrospectively analysed the influence of primary renal disease,gender, urinary protein excretion, mean arterial pressure (MAP),and dietary protein intake on the rate of decline in creatinineclearance (Ccr) in 159 adult patients with well-defined nondiabetickidney diseases. All patients had been followed from a baselineCcr of 40–50 ml/min/1.73 m² until endstage renal diseaseand need for dialysis. RESULTS.: Mean (±SD) Ccr (ml/min/1.73 m²/year) was 9.9±6.5in 51 patients (45 males) with chronic glomerulonephritis, 6±2.5in 50 patients (26 males) with polycystic kidney disease, 5.5±2.4in 17 patients (16 males) with hypertensive angionephrosclerosis,and 3.9±2 in 41 patients (21 males) with chronic tubulointerstitialnephritis. Ccr was higher in males than in females (7.5±5.2versus 4.8±2.5; P <0.001). Linear regression analysisof the whole population disclosed a strong relationship betweenCcr and proteinuria (r² = 0.23; P < 0.001), and a weak relationshipbetween Ccr and protein intake (r² = 0.03; P = 0.02), but norelationship between Ccr and MAP (r² = 0.01; P = 0.23). Stepwisemultiple regression analysis identified the type of nephropathy,gender, and proteinuria as independent predictive factors ofprogression; however, these factors together accounted for only36% of the variation in Ccr, suggesting the contribution ofother yet unidentified factors. CONCLUSIONS.: Primary kidney disease and urinary protein excretion (reflectingthe severity of renal disease in individual cases) appear asthe major determinants of the rate of progression, with fasterprogression in males in all types of nephropathy, whereas potentiallyalterable factors such as blood pressure and protein intakehad only a modest influence in the range of values observedin our patients.     

Enhanced plasma endothelin in healthy uninephrectomized subjects during basal conditions and after indomethacin

Plasma levels of immunoreactive endothelin (ir-ET) at basalresting conditions and the effects of indomethacin (150 mg orally)on the plasma level of ir-ET and renal haemodynamics were evaluatedin 14 healthy uninephrectomized subjects (Unx) and in 14 sex-and age-matched healthy controls subjects (Cs). Glomerular filtrationrate (GFR) and renal plasma flow (RPF) were measured by theconstant infusion clearance technique using ¹²⁵iothalamate and¹³¹I-hippuran as references substances. Immunoreactive endothelinwas measured by radioimmunoassay after prior extraction. At basal resting conditions the plasma level of ir-ET was significantlyhigher in the Unx group. (Unx: 1.28 pmol/l versus Cs: 0.99 pmol/l,P=0.02, medians). After indomethacin the plasma level of ir-ETincreased significantly in both groups and the ir-ET level remainedsignificantly higher in the Unx group compared with the Cs group.Both GFR and RPF decreased significantly after indomethacin(after 120 min: Unx: GFR, –10.9%; RPF, –6.7%; andCs: GFR, –12.5%; RPF, –7.8%, medians). A negativecorrelation in the percentage decrease in GFR (= –0.58,P=0.03) and RPF =–0.61, P=0.03) and the percentage increasein ir-ET 2 h after indomethacin was only found in the Cs group. It is concluded that healthy uninephrectomized subjects havea higher level of ir-ET than healthy controls subjects bothduring basal conditions and after indomethacin. Indomethaciningestion resulted in comparable decreases in renal haemodynamicsin the two groups. It is suggested that the enhanced ir-ET inuninephrectomized subjects could be due to an abnormal renalmetabolism of endothelin in the remnant kidney.     

Renal tubular responses to low-dose infusion of angiotensin II in type 1 diabetes mellitus; relation to chronic glycaemic control

Renal responses to low-dose infusion of angiotensin II (ANGII,1.25 and 2.5 ng.kg^–1 min^–1) were examined in 15patients with type 1 diabetes and in 10 control subjects afterpretreatment with lithium carbonate (750 mg, 20 mmol). Meanarterial pressure rose during ANGII infusion in both groups.The renal haemodynamic response to angiotensin II was not abnormalin the diabetic patients. Absolute proximal reabsorption ofsodium was increased at baseline in the diabetic group, andfell during ANGII. Fractional lithium excretion was reducedin the diabetic patients at baseline (P<0.05), and the fallin fractional lithium excretion during ANGII was less than inthe control group (P=0.012). In the diabetic group correlationsexisted between glycated haemoglobin and baseline glomerularfiltration rate (P<0.05), baseline fractional lithium excretion(P=0.03), and the fall in fractional lithium excretion duringangiotensin II infusion (P=0.013). There was no correlationbetween glycated haemoglobin and absolute lithium clearance.Some indices of sodium reabsorption by the proximal renal tubulein diabetic patients correlate with prevailing chronic glycaemiccontrol, largely reflecting changes in glomerular filtrationrate. Reduced fractional proximal tubular responsiveness toexogenous angiotensin II is consistent with a role for endogenousangiotensin II as one mediator of increased tubular reabsorptionof sodium in type I diabetes, but the data does not excludealternative mechanisms.     

Compliance and effects of nutritional treatment on progression and metabolic disorders of chronic renal failure

Low-protein, low-phosphorus diets (LPD) are prescribed to patientswith chronic renal failure (CRF) to slow down the rate of progressionof CRF and to control uraemic symptoms. A satisfactory adherenceof patients to the prescribed diet is needed to meet these twogoals. We studied the compliance of CRF patients to a LPD providingdaily (per kg body weight) 0.3 g protein, 3–5 mg phosphorus,35 kcal, and supplemented with essential amino-acids and ketoanalogues.Forty CRF patients were studied for 23.3±10.8 months(range 12–45). Compliance to LPD was evaluated by dietaryinquiry and protein intake estimated from urinary urea excretion.According to compliance to LPD, patients were retrospectivelyassigned to the compliant (n=27) or the non-compliant (n=13)group. GFR measured by the urinary clearance of [⁵¹Cr]-EDTAwas identical in the two groups at the start of the study: compliantpatients 15.7±5.3 ml/mn, non-compliant patients 15.4±5.9ml/mn. The decrease of GFR was – 0.08±0.22 ml/minper month in compliant patients versus –0.31±0.37ml/min per month in non-compliant patients (P<0.02). Theseresults were not demonstrated if the progression of CRF wasassessed by the linear regressions over time of creatinine clearanceor the reciprocal of creatinine. Serum bicarbonate, serum phosphorusand PTH levels were corrected by LPD in compliant patients (P<0.005 for all parameters) but not in non-compliant patients.These results suggest that evaluation of compliance is necessaryto assess the response of CRF patients to LPD, whether the aimis to slow the progression of CRF or to control its metabolicconsequences. A beneficial effect of compliance to LPD was demonstratedupon these two goals.     

Cyclosporin does not inhibit the tubular secretion of creatinine

BACKGROUND: The immunosuppressive drug cyclosporin is known to impair renalfunction. The degree of renal dysfunction is usually estimatedfrom the clearance of creatinine (C_Cr). Theoretically however,a fall in C_Cr can be caused by a decrease of GFR, an inhibitionof the tubular secretion of creatinine, or the combination ofboth. CsA has convincingly been shown to decrease GFR, but detailedinformation on the effects of CsA on tubular secretion of creatinineis lacking. METHODS: We performed two studies to investigate the influence of CsAon tubular creatinine secretion. In study A we simultaneouslymeasured C_Cr and GFR (using inulin) immediately before and 4weeks after cessation of CsA therapy in 17 renal transplantpatients. In study B, the rise in serum creatinine after administrationof cimetidine, which blocks the tubular secretion of creatinine,was compared in renal transplant patients treated with eitherCsA (in whom secretion might already be inhibited) or azathioprine. RESULTS: Study A: After cessation of CsA there was an increase of GFR(54±15 vs 63± 16 ml/min/1.73 m²; P>0.01) andof C_Cr (71±21 vs 82±23 ml/min/1.73 m²; P>0.01),but the ratio between C_Cr and GFR (a measure of the relativecontribution of tubular secretion to the clearance of creatinine)did not change significantly (1.33±0.21 vs 1.32±0.30).Study B: In nine couples of patients matched for GFR the relativerises in serum creatinine after administration of cimetidinewere 26±21% and 22±7% for the CsA and azathioprinetreated patients respectively (NS). CONCLUSIONS: CsA does not substantially inhibit the tubular secretion ofcreatinine. A rise in serum creatinine after administrationof CsA can thus be attributed completely to a fall in GFR.     

Effects of cyclosporin A withdrawal on renal function and renal stimulation in liver transplant patients treated with triple-drug immunosuppression for over 2 years

The influence of CsA withdrawal on the glomerular filtrationrate (GFR) and the effective renal plasma flow (ERPF) was prospectivelystudied in nine stable liver transplant recipients. Before CsAwithdrawal (test 1), and 6 months thereafter (test 2) the renalfunction was determined by measuring GFR and the ERPF with ¹²⁵I-iothalamateand ¹³¹I-hippuran respectively. The renal function was alsostimulated with dopamine, with an amino-acid infusion and acombination of both. After CsA withdrawal the GFR increased,median from 74 ml min^–1 to 90 ml min^–1, (P<0.04).The ERPF also increased, median from 310 ml min^–1 to 380ml min^–1, (P<0.03). In test 1 as well as in test 2the renal function could be stimulated, especially with dopamine.GFR and ERPF improved, even after more than 2 years of CsA treatment.These results suggest that long-term CsA treatment impairs therenal function, though in these liver transplant patients CsAtreatment did not prevent afferent and efferent arteriolar vasodilatationafter renal stimulation. This reversible intrarenal vasoconstrictionduring CsA treatment may predict renal improvement after CsAwithdrawal.     

Increased cytosolic free sodium in platelets from patients with early-stage chronic renal failure

Cytosolic free sodium concentration ([Na⁺]i) and sodium transportsystems were measured in intact platelets from 19 patients withearly-stage chronic renal failure and 33 healthy control subjectsusing the novel fluorescent dye sodium-binding-benzofuran-isophthalate.Resting [Na⁺]i was significantly greater in patients with chronicrenal failure compared to control subjects (40.8±3.1mmol/1versus 32.2±2.0 mmol/1, mean±SEM, P<0.05).After inhibition of Na-K-ATPase by 1 mmol/1 ouabain a highernet sodium influx was observed in platelets from patients withchronic renal failure compared to control subjects (49.8±8.7mmol/1 versus 28.5±5.2 mmol/1, P<0.05). The plateletNa-H exchanger was similar in the two groups. Cytosolic freecalcium concentration ([Ca²⁺]i) was measured using fura2 anddid not show significant differences between the two groups.To evaluate whether a circulating factor may be associated withelevated [Na⁺]i, a linked-enzyme Na-K-ATPase assay was included.Compared to control subjects plasma from patients with chronicrenal failure produced a significant inhibition of steady-stateNa-K-ATPase activity by 11.2±3.0% (P<0.01). It isconcluded that early-stage renal failure is associated withsignificant impairment of platelet sodium metabolism.     

Segmental reabsorption measured by micropuncture and clearance methods during hypertonic sodium infusion in the rat

BACKGROUND: We wanted to validate by direct measurements in rat tubulesa technique used to calculate segmental volume absorption byeach segment of the human nephron. METHODS: Experiments were performed on 17 rats during hypertonic Na infusionprior to and after frusemide administration. Tubular sampleswere taken from early distal and last proximal sites. The rateof filtration of single nephrons (SNGFR) was calculated by thetechnique of total collection of tubular fluid using labelledinulin as a marker. Reabsorption was computed by the tubularfluid to plasma (TF/P) inulin concentration ratio. RESULTS: SNGFR was 50±4 nl/min at the distal (n=82), 51±3nl/min at the proximal sampling site (n=112, P>0.65) duringbaseline conditions. Percent reabsorptions were 85±1and 69±2% respectively (P<0.0001). During frusemidethese values were 52±6 nl/min and 76±2% at thedistal, 49±5 nl/min and 66±2% at the proximalsite. In 83 paired proximal collections, fractional (68±1versus 67±1%, P>0.32), absolute reabsorption (34±2versus 33±2, P>0.50) and SNGFR (50±2 nl/minversus 50±3 nl/min, P>0.99) were not different betweenbaseline and frusemide. In 25 re-collections from the distaltubule these same values were 83±2% versus 76±2%,and 48±4 nl/min versus 55±6 nl/min respectively.Very similar results were obtained in 55 paired distalproximalcollections during baseline, and 42 such pairs during frusemide. In the presence of the diuretic the fractional urine excretionwas significantly correlated (R=0.83, P< 0.0001) with fractionalproximal delivery. Na^± resorption by Henle's loop was22±2% calculated from clearance data and 23±1%of GFR from micropuncture data respectively. They were not significantlydifferent (P>0.70) and were significantly correlated (R=0.57,P<0.02). CONCLUSIONS: These data demonstrate that frusemide does not act proximallyand that delivery beyond the proximal tubule approximates urineflow rate during the action of the drug. The values of segmentalreabsorption along the nephron computed on clearance measurementsare superimposable upon those obtained directly by micropuncture.     

The calcitonin-calcium relation curve and calcitonin secretory parameters in renal patients with variable degrees of renal function

Increased calcitonin (CT) levels have been reported in chronicrenal failure, even before the uraemic phase and in the absenceof hypercalcaemia. Furthermore, a sigmoidal CT-calcium relationshipwas recently observed in rats and haemodialysed patients. We carried out the present investigation in order to assess:(a) whether the sigmoidal CT-calcium relationship is also evidentin renal patients with a variable degree of renal failure andin normal subjects; (b) whether the four secretory parametersalready described for the PTH-calcium relation curve might bedescribed for CT too; (c) whether any change in some, if any,of these secretory parameters could be found at a variable degreeof renal insufficiency. We studied 33 renal patients (RP), with a variable degree ofrenal failure (creatinine clearance ranging from 16 to 164ml/min),and 10 normal subjects (C). All RP and C were submitted to abasal evaluation including the assessment of (1) basal concentrationsof 1,25(OH)₂ vitamin D, 25(OH) vitamin D, mono-meric CT, intactPTH; (2) GFR by Cr⁵¹EDTA clearance. On the 2 subsequent days,a hypocalcaemic test (Na₂-EDTA about 37 mg/kg of body-weight/2h) and a hypercalcaemic test (Ca gluconate giving 8 mg/kg body-weight/2h of Ca element) were carried out for the assessment of bothCT and PTH secretory parameters. According to GFR values, theRP were divided into three groups: group RP1 (GFR > 70 ml/minper 1.73 m²; n = 10), group RP2 (GFR between 30 and 70 ml/minper 1.73 m²; n=15), group RP3 (GFR < 30 ml/min per 1.73 m²;n = 8). In most, but not all, RP and C a sigmoidal CT-calcium relationshipwas evident, opposite in direction to the PTH-calcium relationcurve. In these RP and C the four secretory parameters, characteristicfor the PTH-calcium secretion curve, were calculated for CTtoo. When pooled RP and C were considered, both minimal (9.0± 6.4 pg/ml) and maximal CT levels (71.8 ± 56.2pg/ml) significantly differed from basal levels (24.3±18 pg/ml; P<0.001). The CT set point (CT SP) and sensitivity(CT SENS) values were significantly higher and lower than thecorresponding PTH secretory parameters (CT SP 1.39 ±0.08 mmol/1, PTH SP 1.23 ± 0.05 mmol/1,P<0.001) (CTSENS 243 ± 67%/mmol, PTH SENS 598 ± 329%, P<0.001).However, the CT SP values were strictly correlated with PTHSP values (r = 0.78, P<0.001). When CT secretory parameterswere considered separately in the RP groups, increased levelsof basal (36.1±28.6pg/ml), minimal (17.9±10.4),and maximal (139.9 ± 39.7) CT levels were found in theRP3 group, when compared with both the other RP groups and C.No significant difference was found as regards the CT SP andCT SENS values between RP and CT. These results suggest that (1) CT secretion is homeo-staticallycontrolled by calcium changes in the same range of the PTH-calciumsystem; (2) a sigmoidal CT-calcium relationship is demonstrablein most (but not all) RP and C; in these subjects it is possibleto calculate the CT secretory parameters as for PTH; (3) theincrease in CT levels in the course of chronic renal failureis quite similar to the already known increase of PTH, and ischaracterized by the increase of basal, minimal and maximalCT values, suggesting that an increased secretion of CT by thethyroid C-cells (rather than CT retention due to a decreasein renal function), is responsible for these findings.