Chronic renal failure (CRF) is a major organ failure in SCD, probably the consequence of the progression of focal segmental glomerulosclerosis (FSGS). Overall, 5–18% of SCD patients will develop CRF.
Hyperfiltration is recognized in SCD by increased GFR, especially in children. An even greater increase in effective renal plasma flow (ERPF) (all plasma that goes through the filtering units) results in a lower than normal filtration fraction, the proportion of a substance flowing through the kidney that is filtered. Increased cortical blood flow itself could cause decreased tubular secretion by limiting diffusion from rapidly flowing plasma. Alternatively, a distinctive increased glomerular permeability (tested by dextrans) may exist in SCD nephropathy, not explained by purely hemodynamic changes. Proximal tubular “hyperfunction” in SCD may be a compensation for the distal tubular injury, mediated by the PG systems (see above). The net effect of PG inhibition is to reverse hyperfiltration. The dramatically increased ERPF and decreased filtration fraction of SCD are returned toward normal. If hyperfiltration is a necessary predecessor of glomerulopathy in SCD, then prostaglandins may explain the early development of FSGS.
Glomerulopathy in SCD has been attributed to immunopathogenic mechanisms, because of a reported membranoproliferative glomerulonephritis (MPGN). However, most now agree that evidence of immune complex deposition is usually lacking in SCD patients with heavy proteinuria.
Possible mechanisms of the SCD nephropathy associated with FSGS include hyperfiltration and glomerular hypertrophy. Hyperfiltration, combined with direct endothelial damage by occlusion with sickled cells, might lead to endothelial hyperplasia and ultimately fibrosis. Any hypothesis should take into account that glomerular hypertrophy is always present in SCD, probably related to the anemia itself, but proteinuria is not invariable in SCD and appears to be unrelated to the number and severity of SCD crises or the presence of hematuria or demonstrated RPN.
Systemic hypertension is notably absent in these patients. The presence of hyperfiltration, glomerular hypertrophy, and FSGS does not imply that these findings are sequential or causative. A common stimulus may be operative, such as the growth-promoting hormones and inflammatory cytokines, to which the glomerulus may be sensitive. It is possible that FSGS is the consequence rather than the cause of interstitial fibrosis, which might obstruct the efferent glomerular capillaries, raising intraglomerular pressure and resulting in progressive (reactive) sclerosis.
The iron deposited as hemosiderin in tubular cells has been suspected of playing a role in the chronic nephropathy of SCD, but the mechanism is not clear. Experimentally, saturated iron complexes can induce a nephrotic syndrome in rabbits.
The prevention of sickle cell nephropathy (SCN), or preventing its progression, may involve measures to prevent both sickle crises and hyperfiltration (see below).
The association of significant proteinuria with SCD was often recognized sporadically and usually described as a nephritic process.
The definition of SCN that is most accepted now is associated with nephrotic-range proteinuria. While long-term studies have not been done, it appears to have a more rapid course than other causes of nephrotic syndrome. Two-thirds of patients developed renal failure within 2 years. The onset of renal failure was heralded by increasingly inadequate erythropoiesis, and carried a survival time of 4 years.
Hyperfiltration complicates the estimation of GFR, whose upper limits of the normal range are not certain even with the “gold standard” of inulin clearance. The reliability of the clearance methods that can substitute for inulin clearance have certainly not been validated in the elevated range. For most clinical purposes, an accurate measure of GFR is unnecessary. A decrease in GFR, particularly when accompanied by proteinuria, is ominous.
For clinical purposes, renal ultrasound should be adequate to estimate kidney size and to exclude the likelihood of renal medullary carcinoma (see Figure 49–1).
The usual glomerular finding in sickle cell nephropathy is FSGS, which is intimately associated with glomerular hypertrophy. Immunofluorescence is positive only for IgM, C3, and C1q irregularly in sclerotic segments. Electron microscopy confirms the absence of immune complex-type dense deposits. There was focal electron-lucent expansion of the subendothelial zone with occasional mesangial cell interposition. No new mesangial matrix material is observed to suggest MPGN.
Proteinuria detected by dipstick in a patient with SCD should be quantified and renal function assessed. Diseases other than sickle cell glomerulopathy should be considered. If hematuria is present, RBC casts may point to pathology other than sickle cell glomerulopathy. Hypertension, hypocomplementemia, and antinuclear antibodies also suggest other diagnoses. Judging from the relatively uniform findings in our series, few other additional studies are indicated. Microalbuminuria has been found in SCD patients >9 years of age, and may predict those with future glomerulopathy.
- Slowing the progression of SCN to chronic renal insufficiency (CRI) in SCD involves modifications in physiology, which also affect growth factors.
- Efforts to reduce sickling crises are of unknown value.
- Renal transplantation for end-stage kidney failure can dramatically improve patient survival compared to dialysis.
The patients with proteinuria in our series were not those with either the most frequent sickle crises or the severest anemia. Nevertheless, some factors in the sickle cell condition must predispose to the nephropathy. Therefore, it is reasonable to attempt to minimize sickling and those factors known to promote FSGS in other primary diseases or in animal models, but it is unknown whether hemodynamic alterations can alter the progression of FSGS to CRI.
Because high protein intake accelerates the development of FSGS in uninephrectomized rats, without necessarily causing glomerular hyperperfusion, it is attractive to consider protein restriction in the management of SCD nephropathy, as is being tried in several forms of renal disease. In children, restriction of protein intake may carry unreasonable risks. Delayed growth and development are already particular risks in the patient with SCD. Therefore, we advise only the avoidance of an unusually high protein intake that is greater than the recommended dietary allowance.
Angiotensin-Converting Enzyme Inhibition
Glomerular hyperperfusion and proteinuria could be mediated through increased glomerular capillary pressure, reduction of which by ACE inhibition might protect the glomerulus from FSGS.
In our 2-week trial of enalapril therapy in 10 patients with mild SCD nephropathy, blood pressure, GFR (CIn), and ERPF (p-aminohippuric acid clearance) did not change significantly, whereas proteinuria diminished by 57%, rebounding after treatment withdrawal. A more recent 6-month controlled trial of enalapril in 22 SCD patients with microalbuminuria showed a significant decrease in the treatment group, while the control group increased. Whether long-term ACE inhibitor therapy has a salutary effect in preventing renal insufficiency is untested.
Specific treatment of the patient with SCD and renal failure has been poorly explored, and the problems of CRI are only magnified by SCD. Patients with renal failure, even mild, can have symptomatic anemia requiring transfusion. In some patients, treatment with erythropoietin can variably restore hemoglobin concentrations to higher levels. A few patients have been treated with hydroxyurea plus erythropoietin with apparent benefit.
Dialysis and Transplantation
Renal transplantation is a better option than long-term dialysis for the SCD patient with CRI.
In our review of the U.S. Renal Data System files for 2000, we found 1656 SCD patients, 237 transplanted and 1419 not transplanted, who did not have causes of CRI other than likely SCN. While in the transplanted SCD patient survival was worse than that of all African-American patients without SCD, the lifetable projected survival times were still quite close, with approximately 50% survival at 15 years. Using an age-adjusted cohort of African-American patients as controls, the difference statistically disappeared. Comparing the nontransplanted SCD patients with the cohort of African-American patients, survival was quite different, but both were extremely poor: 14% for SCD patients and 25% for African-American patients at 10 years. A comparison of the 153 transplanted SCD patients with those who received no transplant showed a far better survival curve, 56% versus 14% at 10 years.
These results indicate that transplantation is a better option for the SCD patient with renal failure. However, results may be less satisfactory than for other African-American patients, and grafts have been lost due to demonstrable massive sickling events.
Bone marrow transplantation can cure SCD, and the possibility of its coupling with other transplants will undoubtedly be explored. Caution will be needed, in view of the possible increase in parvovirus, a common agent of aplastic crisis that might be especially dangerous in the transplant patient.
Animal experiments have shown the promise of genetic transduction of an antisickling hemoglobin to cure sickling in mice.
Datta V et al: Microalbuminuria as a predictor of early glomerular injury in children with sickle cell disease. Indian J Pediatr 2003;70:307.
Papassotiriou I et al: Increased erythropoietin level induced by hydroxyurea
treatment of sickle cell patients. Hematol J 2000;1:295.