Pancreas-kidney transplantation is increasingly considered the gold standard for treatment of severe diabetic nephropathy (1–2). Early preemptive approaches are advocated to stop and reverse the long-term consequences of diabetes mellitus (3–5).
Although the follow-up of retinopathy and neuropathy have been extensively studied, less is known about the outcome of the nephrotic syndrome characterizing advanced diabetic nephropathy (4,5). Reversal of the renal lesions years after pancreas transplantation has been documented, whereas reduction of the proteinuria with regained metabolic control has been reported after isolated pancreas grafts (6). The largest analysis of the functional contribution of the native kidneys after preemptive pancreas-kidney transplantation failed to provide information on proteinuria (7). The reversal of proteinuria has been described in a few Congress reports, but has never been extensively studied (8).
This is a minor issue if transplantation is performed in the late stages of diabetic nephropathy, when the nephrotoxicity of immunosuppressive drugs may rapidly extinguish the native renal function and consequently reduce proteinuria. However, it becomes important when transplantation is performed in the earlier stages of functional impairment, particularly when the choice of transplantation is mainly motivated by a severe nephrotic syndrome.
The present report on rapid reversal of the nephrotic syndrome in two patients with diabetic nephropathy who underwent early preemptive pancreas-kidney and kidney transplantation focuses attention on this important therapeutic result (never before described in detail) and gives some insight into the mechanism of action.
A 42-year-old woman, with type 1 diabetes since the age of 24 years, was referred to the department of nephrology in 1999 with nephrotic proteinuria. She demonstrated widespread end-organ damage: retinopathy (laser-treated and vitrectomized, with visual impairment), neuropathy, and hypertension.
At referral, a renal scintiscan (99mTc-MAG3) under angiotensin-converting enzyme (ACE) inhibitor displayed kidneys of normal size, homogeneous function, and normal parenchymal phases (September 1999: serum creatinine 1.3 mg/dL, creatinine clearance 55.2 mL/min, proteinuria 2–4 g/24 hr) (Fig. 1).
A renal biopsy, performed in March 2001 after a full-blown nephrotic phase (proteinuria 9 g/day), showed nodular-diffuse diabetic nephropathy. She was started on a low-protein, vegetarian diet. Her arterial blood pressure was normal (110–130/70–80 mm Hg) under ACE-inhibitors (Enalapril 20 mg) and angiotensin II receptor antagonists (Candesartan 8 mg).
In 2002, she was wait-listed for pancreas-kidney transplantation; in February 2003, she received a successful pancreas-kidney graft. The last controls before transplantation were the following: serum creatinine 1.6 mg/dL, creatinine clearance 58 mL/min, serum albumin 2.9 g/dL, total proteins 5.7 g/dL, proteinuria 9.1 g/24 hr, hemoglobin 12.9 g/dL, and glycated hemoglobin 11.2%. Proteinuria displayed a glomerular nonselective, tubular complete pattern.
At hospital discharge (22 days later), she was euglycemic (serum creatinine 1.2 mg/dL, creatinine clearance 97 mL/min, and proteinuria 0.6 g/24 hr).
Induction antirejection therapy was basiliximab 20 mg/day and methylprednisolone 500 mg.
Maintenance therapy was FK 506 (levels 9–12 ng/mL), mycophenolic acid (2 g), and prednisone tapered to 5 mg/day at the sixth month. Proteinuria, ranging from 0.3 to 0.6 g/24 hr, had a physiologic pattern. A renal scintiscan (99mTc-MAG 3) in April 2003 demonstrated almost complete functional exclusion of the native kidneys, each of which contributed 11% of the overall function, as assessed by plasma flow (Fig. 1).
A 48-year-old man, with type 2 diabetes diagnosed at age 37 years, was referred to the department of nephrology in 2001 because of nephrotic syndrome in a single kidney (right nephrectomy of a pelvic pyelonephritic kidney in 1997) (Fig. 2). Before nephrectomy, serum creatinine was 1.1 mg/dL, creatinine clearance was 141 mL/min, and proteinuria was 2 g/24 hr. In the following years (1997–2001), he demonstrated renal functional impairment and nephrotic syndrome. At referral, creatinine ranged from 1.3 to 1.8 mg/dL and proteinuria ranged from 4 to 10 g/day, with wide variations, partly dependent on glycemic control. Diffuse end-organ damage was present (laser-treated retinopathy, neuropathy, and hypertension).
A renal biopsy in 2002 confirmed the presence of diabetic nephropathy (diffuse pattern) with ischemic glomerular and tubulointerstitial damage.
In February 2003, he was wait-listed for pancreas-kidney transplantation, and in April 2003 he received a preemptive renal graft (with a “kidney nobody wants” from a donor with positive anamnesis for cocaine and cannabis abuse, and with negative HIV-polymerase chain reaction testing). This choice, extensively discussed with the patient, was motivated by the availability of an organ considered suitable only for lifesaving grafts (history of drug abuse). One kidney and the pancreas were grafted at the same center; the second kidney was offered to our patient within a program of pancreas after kidney graft.
The last renal functional profile before transplantation showed the following: serum creatinine 2 mg/dL, creatinine clearance 62 mL/min, serum albumin 3.5 g/dL, proteinuria 5.9 g/24 hr, hemoglobin 11.3 g/dL, and glycated hemoglobin 7.9%. Proteinuria had a glomerular nonselective, tubular complete pattern. Hypertension was controlled by enalapril 20 mg and candesartan 8 mg. Induction antirejection therapy was the same as in case 1.
At hospital discharge (1 month after transplantation), serum creatinine was 1.1 mg/dL, creatinine clearance was 117 mL/min, serum albumin was 3.8 g/dL, hemoglobin was 12.2 g/dL, and glycated hemoglobin was 9.1%. Proteinuria was 0.7 g/24 hr with a glomerular selective, incomplete tubular pattern, compatible with “overflow” reversible proteinuria typical of hyperfiltration states (presumably linked to the poor metabolic control). A renal scintiscan showed almost complete functional exclusion of the native kidney, which contributed 18% of the overall function (Fig. 2).
CASES 3 AND 4
Case 3 was a 45-year-old woman, with type 1 diabetes since age 14 years, demonstrating biopsy-proven diabetic nephropathy (1997, nodular and diffuse pattern), laser-treated retinopathy, hypertension (receiving enalapril 20 mg), and neuropathy.
In April 2003, she underwent an isolated pancreas graft in the same center (Pisa, Italy). Before transplantation, serum creatinine was 1 mg/dL, creatinine clearance was 108 mL/min, proteinuria was 0.3 g/day, and glycated hemoglobin was 7.2%; at hospital discharge (1 month later), creatinine was 0.8 mg/dL and proteinuria was 0.3 g/day. Induction and maintenance therapy followed the same protocol as in cases 1 and 2.
The results of a renal scintiscan in June 2003 were the same as those of a scintiscan in 1997.
The same pattern (stability of the renal function and of renal scintiscan before and after isolated pancreas transplantation) was observed in case 4, a 49 year-old woman, with a clinical diagnosis of diabetic nephropathy (microalbuminuria and low-normal renal function), who underwent grafting in the same setting on the same therapeutic regimen.
In the first two cases, the main indication for a preemptive pancreas-kidney graft was the presence of a nephrotic syndrome not responsive to ACE-inhibitors, angiotensin II receptor antagonists, normotension, and a low-protein diet.
The major finding was a rapid, complete reversal of the nephrotic syndrome within 1 month after transplantation (pancreas-kidney in case 1, kidney in case 2). Proteinuria decreased from 6 to 9 g per day to less than 1 g in both cases (0.3–0.7 g/day), and its pattern changed from a glomerular nonselective, tubular complete pattern to a physiologic pattern in case 1 (euglycemic) and a hyperfiltration pattern in case 2 (poor diabetes control). The morpho-functional scintigraphic study, performed in the same setting and by the same operators before and after transplantation, indicated the almost complete functional exclusion of the native kidneys in both cases. The effect was not related to euglycemia, because it was also observed in case 2, who received only a kidney graft in anticipation of a subsequent pancreas transplantation. No change was recorded in cases 3 and 4, who underwent an isolated pancreas graft in the same setting (biopsy-proven and clinical diagnosis of diabetic nephropathy, without functional impairment).
The reversal of the nephrotic syndrome is of particular interest, because the two patients had well-preserved renal function, with creatinine clearance of 50 to 60 mL/min. Therefore, they had an expected kidney function survival of at least 5 years, based on the “classic” literature data of a functional decrease of 10 mL/min of creatinine clearance per year (9), or even of approximately 10 years considering our data of approximately −4 mL/min per year. Both patients were treated with ACE inhibitors, angiotensin II receptor antagonists, and a low-protein vegetarian diet. The combination of these three elements act to reduce the hyperfiltration states, and their withdrawal after transplantation would be expected to lead to an increase in glomerular filtration rate, in contrast with what was observed.
In such functional conditions, even major surgery is not expected to induce persistent renal failure.
The nephrotoxic effect of calcineurin inhibitors is an important issue. The nephrotoxicity and anti-proteinuric effect of chronic therapies usually has a slower onset; it is witnessed both by the slow renal function impairment occurring after non-renal grafts and by the delayed effect on proteinuria, recorded in primary renal diseases, in which calcineurin inhibitors are used at similar functional levels (10,11). Furthermore, an aspecific nephrotoxic effect linked to the surgical or anesthesiologic procedures or to calcineurin inhibitors, in the context of the immunodepressive protocols used, seems unlikely, at least as a single cause, because of the lack of modifications in the third patient with biopsy-proven diabetic nephropathy and in one further case with clinical diagnosis of initial renal damage, treated by the same protocol. Their renal function was unaffected, and the morpho-functional pattern was unmodified by the pancreatic graft, performed with the same protocols in the same setting.
From the clinical point of view, this functional pattern confirms a therapeutic role of preemptive transplantation in the care of one of the most serious complications of diabetes: nephrotic syndrome. On a speculative note, because these findings were unrelated to euglycemia and not linked to aspecific postsurgical or nephrotoxic effects, the possible role of a still unclear hemodynamic mechanism merits further investigation.
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